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Sample records for 5-day repeated-dose study

  1. Acute and repeated dose toxicity studies of different β-cyclodextrin-based nanosponge formulations.

    PubMed

    Shende, Pravin; Kulkarni, Yogesh A; Gaud, R S; Deshmukh, Kiran; Cavalli, Roberta; Trotta, Francesco; Caldera, Fabrizio

    2015-05-01

    Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals.

  2. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

    PubMed

    Dent, M P

    2007-08-01

    The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert

  3. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  4. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  5. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  6. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  7. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... study with the reproduction/developmental toxicity screening test. 799.9365 Section 799.9365 Protection... § 799.9365 TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity... all aspects of reproduction and development. In particular, it offers only limited means of...

  8. A 13-week dermal repeat-dose neurotoxicity study of hydrodesulfurized kerosene in rats.

    PubMed

    Breglia, Rudolph; Bui, Quang; Burnett, Donald; Koschier, Francis; Lapadula, Elizabeth; Podhasky, Paula; Schreiner, Ceinwen; White, Russell

    2014-01-01

    A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

  9. Validation study of the combined repeated-dose toxicity and genotoxicity assay using gpt delta rats.

    PubMed

    Akagi, Jun-Ichi; Toyoda, Takeshi; Cho, Young-Man; Mizuta, Yasuko; Nohmi, Takehiko; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2015-05-01

    Transgenic rodents carrying reporter genes to detect organ-specific in vivo genetic alterations are useful for risk assessment of genotoxicity that causes cancer. Thus, the Organization for Economic Co-operation and Development has established the guideline for genotoxicity tests using transgenic animals, which may be combined with repeated-dose toxicity studies. Here, we provide evidence to support equivalence of gpt delta and wild type (WT) rats in terms of toxicological responses to a genotoxic hepatocarcinogen, N-nitrosodiethylamine (DEN), and a non-genotoxic hepatocarcinogen, di(2-ethylhexyl)phthalate (DEHP). gpt delta rats treated with DEHP showed similar increases in liver and kidney weights, serum albumin, albumin/globulin ratios, and incidence of diffuse hepatocyte hypertrophy compared to WT F344 and Sprague-Dawley (SD) rats. DEN-treated gpt delta rats showed equivalent increases in the number and area of precancerous GST-P-positive foci in the liver compared to WT rats. The livers of DEN-treated gpt delta rats also showed increased frequencies of gpt and Spi(-) mutations; such changes were not observed in DEHP-treated gpt delta rats. These results indicated that gpt delta rats (both F344 and SD backgrounds) showed comparable DEHP-induced toxicity and DEN-induced genotoxicity to those observed in WT rats. With regard to the administration period, the general toxicity of 1.2% DEHP was evident throughout the experimental period, and the genotoxicity of 10 p.p.m. DEN could be detected after 2 weeks of administration and further increased at 4 weeks. These results suggested that combined assays using gpt delta rats could detect both general toxicity and genotoxicity by the canonical 4-week administration protocol. Therefore, this assay using gpt delta rats would be applicable for risk assessment including early detection of genotoxic carcinogens and ultimately serve to reduce cancer risks in humans from environmental chemicals.

  10. A repeated dose 90-day oral toxicity study of cyflumetofen,a novel acaricide, in rats.

    PubMed

    Yoshida, Toshinori; Ikemi, Naoki; Takeuchi, Yukiko; Ebino, Koichi; Kojima, Sayuri; Chiba, Yuko; Nakashima, Nobuaki; Kawakatsu, Hisao; Saka, Machiko; Harada, Takanori

    2012-02-01

    Cyflumetofen is a novel acaricide which is highly active against phytophagous mites. As a part of safety assessment, a repeated dose 90-day oral toxicity study of cyflumetofen was conducted in Fischer (F344/DuCrj) rats of both sexes. Technical grade cyflumetofen was administered in feed to groups of 10 males and 10 females at dose levels of 0, 100, 300, 1,000, and 3,000 ppm. Prothrombin time was prolonged in males at 3,000 ppm and plasma globulin levels were decreased in females at 1,000 and 3,000 ppm. At necropsy, enlarged and whitish adrenals were observed in females at 3,000 ppm. There were statistically significant increases in relative liver weight (ratio to body weight) in males and relative adrenal weight in females in the 1,000 ppm group; increased relative liver and kidney weights in both sexes at 3,000 ppm, and increased absolute and relative weights of adrenals in females at 3,000 ppm. Increased absolute liver weight was also noted in males at 3,000 ppm. Histopathologically, at 1,000 and 3,000 ppm males had diffuse vacuolation and females had diffuse hypertrophy of adrenal cortical cells. In addition, vacuolation of ovarian interstitial gland cells was noted in females at 1,000 and 3,000 ppm. There were no treatment-related changes in any parameters for either sex in other dose groups. Based on these results, the no-observed-adverse-effect level (NOAEL) of cyflumetofen was judged to be 300 ppm for both sexes (16.5 mg/kg/day for males and 19.0 mg/kg/day for females).

  11. Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae) in Swiss Mice

    PubMed Central

    Freire Rocha Caldas, Germana; Araújo, Alice Valença; Albuquerque, Giwellington Silva; Silva-Neto, Jacinto da Costa; Costa-Silva, João Henrique; de Menezes, Irwin Rose Alencar; Leite, Ana Cristina Lima; da Costa, José Galberto Martins; Wanderley, Almir Gonçalves

    2013-01-01

    Hyptis martiusii Benth. (Lamiaceae) is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM). Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg) for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice. PMID:24151521

  12. Preliminary pharmacokinetic study of repeated doses of rifampin and rifapentine in guinea pigs.

    PubMed

    Dutta, Noton K; Alsultan, Abdullah; Peloquin, Charles A; Karakousis, Petros C

    2013-03-01

    Substitution of rifapentine (RFP) for rifampin (RIF) in the standard antituberculous regimen reduces the time required to cure chronic tuberculosis (TB) infection in mice, but not in guinea pigs. In order to gain insight into these discrepant findings, we conducted a steady-state pharmacokinetic (PK) study in healthy guinea pigs to study the metabolism and autoinduction of RIF and RFP. Both RFP and RIF 25-desacetyl metabolites (desRFP and desRIF, respectively), were detected at low concentrations in the serum of guinea pigs. The metabolite concentrations in guinea pigs are much lower than those seen in humans at steady state.

  13. Preliminary Pharmacokinetic Study of Repeated Doses of Rifampin and Rifapentine in Guinea Pigs

    PubMed Central

    Dutta, Noton K.; Alsultan, Abdullah; Peloquin, Charles A.

    2013-01-01

    Substitution of rifapentine (RFP) for rifampin (RIF) in the standard antituberculous regimen reduces the time required to cure chronic tuberculosis (TB) infection in mice, but not in guinea pigs. In order to gain insight into these discrepant findings, we conducted a steady-state pharmacokinetic (PK) study in healthy guinea pigs to study the metabolism and autoinduction of RIF and RFP. Both RFP and RIF 25-desacetyl metabolites (desRFP and desRIF, respectively), were detected at low concentrations in the serum of guinea pigs. The metabolite concentrations in guinea pigs are much lower than those seen in humans at steady state. PMID:23295923

  14. 28-Day repeated dose toxicity study of dried microorganism in rats.

    PubMed

    Kitano, M; Hosoe, K; Fukutomi, N; Hidaka, T; Imai, N; Kawabe, M

    2004-11-01

    Ubidecarenone, also known as CoQ(10), is currently sold as a dietary supplement in the United States, with a majority of these products derived from the fermentation of carbohydrates or tobacco leaf extracts. In addition to its availability in dietary supplements, CoQ(10) is now being considered for use in foods. Accordingly, as part of the process for attaining "Generally Recognized as Safe" status, and to supplement information already available regarding the safety of CoQ(10) per se, a 28-day oral toxicity study in rats was conducted to evaluate the subacute safety of a microorganism biomass used as a new source in CoQ(10) production. Groups of Crj:CD(SD) rats (SPF) (6 males or females per group, 4 groups per sex) received dried microorganism at doses of 0, 500, 1000 or 2000 mg/kg/day via intragastric intubation. Clinical observations were recorded, and body weight, and food and water consumptions measured throughout the study. At the end of the study, aortic blood samples were collected from all animals for analysis of hematological and clinical chemistry parameters, and gross pathologic examination was performed. Histopathologic examination was performed on select tissues from the control and high-dose groups. There were no treatment-related changes that were considered to be of toxicological significance. Since rats treated with 2000 mg/kg of dried microorganism did not demonstrate any treatment-related changes, the no-observable-adverse-effect level (NOAEL) for dried microorganism was estimated to be greater than 2000 mg/kg/day under the present study conditions.

  15. Acute toxicity and the 28-day repeated dose study of a Siddha medicine Nuna Kadugu in rats

    PubMed Central

    2012-01-01

    Background Nuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats. Methods Acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed. Results In acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment. Conclusion Acute study reveals that the LD50 of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects

  16. A fourteen-day repeated dose oral toxicity study of APFO in rats.

    PubMed

    Iwai, Hiroyuki; Yamashita, Kotaro

    2006-01-01

    Ammonium perfluoroocanoate (APFO) was repeatedly administered orally to male Crj:CD(SD)IGS rats for 14 days. Doses of APFO were 0, 0.5, 5, and 50 mg/kg. Significant increases and increasing tendencies in absolute/relative weight of the liver and no change in weight of the spleen were observed in all groups. Although inductions of mitochondrion- and peroxisome-specific enzymes were increased, no decrease was seen in any hematological parameter of lipid metabolism. Red blood cell count, hemoglobin concentration, and hematocrit or these tendencies showed a significant decrease or a tendency to decrease, but no influence on lymphocyte subsets was noted. Secondary inhibition of immunocompetent cells, previously reported for mice, was not seen in this study of rats.

  17. Zinc oxide nanoparticles: a 90-day repeated-dose dermal toxicity study in rats

    PubMed Central

    Ryu, Hwa Jung; Seo, Mu Yeb; Jung, Sung Kyu; Maeng, Eun Ho; Lee, Seung-Young; Jang, Dong-Hyouk; Lee, Taek-Jin; Jo, Ki-Yeon; Kim, Yu-Ri; Cho, Kyu-Bong; Kim, Meyoung-Kon; Lee, Beom Jun; Son, Sang Wook

    2014-01-01

    Zinc oxide (ZnO) works as a long-lasting, broad-spectrum physical sunblock, and can prevent skin cancer, sunburn, and photoaging. Nanosized ZnO particles are used often in sunscreens due to consumer preference over larger sizes, which appear opaque when dermally applied. Although the US Food and Drug Administration approved the use of nanoparticles (NPs) in sunscreens in 1999, there are ongoing safety concerns. The aim of this study was to evaluate the subchronic toxicity of ZnO NPs after dermal application according to the Organization for Economic Cooperation and Development Test Guidelines 411 using Good Laboratory Practice. Sprague Dawley rats were randomly divided into eight (one control, one vehicle control, three experimental, and three recovery) groups. Different concentrations of ZnO NPs were dermally applied to the rats in the experimental groups for 90 days. Clinical observations as well as weight and food consumption were measured and recorded daily. Hematology and biochemistry parameters were determined. Gross pathologic and histopathologic examinations were performed on selected tissues from all animals. Analyses of tissue were undertaken to determine target organ tissue distribution. There was no increased mortality in the experimental group. Although there was dose-dependent irritation at the site of application, there were no abnormal findings related to ZnO NPs in other organs. Increased concentrations of ZnO in the liver, small intestine, large intestine, and feces were thought to result from oral ingestion of ZnO NPs via licking. Penetration of ZnO NPs through the skin seemed to be limited via the dermal route. This study demonstrates that there was no observed adverse effect of ZnO NPs up to 1,000 mg/kg body weight when they are applied dermally. PMID:25565832

  18. Repeated dose titration versus age-based method in electroconvulsive therapy: a pilot study.

    PubMed

    Aten, Jan Jaap; Oudega, Mardien; van Exel, Eric; Stek, Max L; van Waarde, Jeroen A

    2015-06-01

    In electroconvulsive therapy (ECT), a dose titration method (DTM) was suggested to be more individualized and therefore more accurate than formula-based dosing methods. A repeated DTM (every sixth session and dose adjustment accordingly) was compared to an age-based method (ABM) regarding treatment characteristics, clinical outcome, and cognitive functioning after ECT. Thirty-nine unipolar depressed patients dosed using repeated DTM and 40 matched patients treated with ABM were compared. Montgomery-Åsberg Depression Rating Scale (MADRS) and Mini-Mental State Examination (MMSE) were assessed at baseline and at the end of the index course, as well as the total number of ECT sessions. Both groups were similar regarding age, sex, psychotic features, mean baseline MADRS, and median baseline MMSE. At the end of the index course, the two methods showed equal outcome (mean end MADRS, 11.6 ± 8.3 in DTM and 9.5 ± 7.6 in ABM (P = 0.26); median end MMSE, 28 (25-29) and 28 (25-29.8), respectively (P = 0.81). However, the median number of all ECT sessions differed 16 (11-22) in DTM versus 12 (10-14.8) in ABM; P = 0.02]. Using regression analysis, dosing method and age were independently associated with the total number of ECT sessions, with less sessions needed in ABM (P = 0.02) and in older patients (P = 0.001). In this comparative cohort study, ABM and DTM showed equal outcome for depression and cognition. However, the median ECT course duration in repeated DTM appeared longer. Additionally, higher age was associated with shorter ECT courses regardless of the dosing method. Further prospective studies are needed to confirm these findings.

  19. 28-day repeated dose response study of diglycolic acid: Renal and hepatic effects.

    PubMed

    Sprando, Robert L; Mossoba, Miriam E; Black, Thomas; Keltner, Zachary; Vohra, Sanah; Olejnik, Nicholas; Toomer, Howard; Stine, Cynthia; Evans, Eric; Sprando, Jessica L; Ferguson, Martine

    2017-03-25

    The acute oral toxicity of diglycolic acid (DGA) was evaluated. Groups of female rats (n = 8 rats/group) received 28 consecutive daily single doses of 0.3, 1.0, 3.0, 10.0, 30.0, 100.0 or 300.0 mg DGA/kg body weight by gastric intubation. One group of animals served as vehicle control. Tissues and blood serum were collected at necropsy on day 29. Select organs were weighed and fixed in formalin for histopathological analysis. Animals from the 300 mg/kg bw dose group were removed from the study after 5 consecutive days of treatment as a consequence of adverse treatment related effects. The animals in the remaining treatment groups survived the exposure period. No adverse clinical signs were observed throughout the exposure period in the surviving animals. No significant differences from controls were observed for feed and fluid consumption or body weight gain in the surviving animals. Lesions were observed in the kidneys, liver, stomach, intestine, thymus, spleen and bone marrow in animals from the 300 mg/kg dose group and signs of renal tubular regeneration were observed only in the 100 mg/kg dose group. These results suggest that high levels of pure DGA would need to be consumed before renal and other forms of organ toxicity are observed.

  20. Repeated dose (14 days) rat intramuscular toxicology study of Her1 vaccine.

    PubMed

    Mancebo, A; Casacó, A; Sánchez, B; González, B; Gómez, D; León, A; Bada, A M; Arteaga, M E; González, Y; González, C; Pupo, M; Fuentes, Dasha

    2012-12-01

    Our goal was to assess the toxicity of two strengths (200 and 400 μg) of HER1 cancer vaccine (Center of Molecular Immunology, Cuba), presented in two different formulations, in Sprague Dawley rats after repeated intramuscular administration (14 days). Four groups (5 animals/sex) were established: Control, Placebo (adjuvant), and two Treated groups receiving a dose representing ten times of human total dose (10×), 28.6 and 57.1 μg/kg. Clinical observations, body weight and rectal temperature were measured during the study. Clinical pathology analysis was performed, besides gross necropsy and histological examination of tissues on animals at the end of the assay. The assay ended with a 100% survival. Injection site damage, with the presence of cysts and granulomas, was observed in adjuvant and vaccine treated groups, with most severe cases predominating at higher strength. Administration of Placebo and Her1 vaccine induced increase in polymorphonuclear cells, with relative lymphopenia conditioned by primary neutrophilia. In summary, results suggest that Her1 immunization was capable of inducing an inflammatory effect at the injection site, leading to systemic alterations, more significant at higher strength (400 μg, 57.1 μg/kg), probably affected by the immunizations' schedule used. The vaccine was shown to be well tolerated without any obvious signs of systemic toxicity, with findings largely attributable to the adjuvant used.

  1. Preclinical safety evaluation of IQG-607 in rats: Acute and repeated dose toxicity studies.

    PubMed

    Rodrigues-Junior, Valnês S; Machado, Pablo; Calixto, João B; Siqueira, Jarbas M; Andrade, Edinéia; Bento, Allisson; Campos, Maria M; Basso, Luiz A; Santos, Diógenes S

    2017-02-20

    In the present study, we evaluated the safety and the possible toxic effects of IQG-607 after acute and 90-day repeated administrations in rats. Single oral administration of IQG-607 (300 or 2000 mg/kg) on female rats did not result in any mortality. No gross lesions were observed in the animals at necropsy. Ninety-day administration test resulted in 20% of deaths, in both male and female rats administered with the highest dose of IQG-607, 300 mg/kg. Repeated administration of the IQG 607 (25, 100 and 300 mg/kg) did not result in any significant body mass alteration, or changes in food and water consumption. The most important clinical sign observed was salivation in both sexes. Importantly, long-term treatment with IQG-607 did not induce alterations in any hematological (for both sex) and serum biochemical (for female) parameters evaluated, even at the highest dose tested. Treatment of male rats with 100 or 300 mg/kg of IQG-607 decreased total cholesterol levels, while animals treated with 100 mg/kg also presented reduction on triglyceride levels. Of note, no treatment induced significant histopathological alterations in tissues of all organs and glands analyzed, even in that group that received the highest dose of IQG-607.

  2. Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study

    NASA Astrophysics Data System (ADS)

    Kura, Aminu Umar; Cheah, Pike-See; Hussein, Mohd Zobir; Hassan, Zurina; Tengku Azmi, Tengku Ibrahim; Hussein, Nor Fuzina; Fakurazi, Sharida

    2014-05-01

    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant ( p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant ( p < 0.05) compared to the control (0.51 ± 0.07). Histology of the liver, spleen and brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated

  3. Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study

    PubMed Central

    2014-01-01

    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant (p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant (p < 0.05) compared to the control (0.51 ± 0.07). Histology of the liver, spleen and brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in

  4. Evaluation of a repeated dose liver micronucleus assay in rats treated with two genotoxic hepatocarcinogens, dimethylnitrosamine and 2-acetylaminofluorene: the possibility of integrating micronucleus tests with multiple tissues into a repeated dose general toxicity study.

    PubMed

    Takashima, Rie; Takasawa, Hironao; Kawasako, Kazufumi; Ohyama, Wakako; Okada, Emiko; Narumi, Kazunori; Fujiishi, Yohei; Wako, Yumi; Yasunaga, Katsuaki; Hattori, Akiko; Kawabata, Masayoshi; Nakadate, Kiyoko; Nakagawa, Munehiro; Hamada, Shuichi

    2015-03-01

    As part of a collaborative study by the Collaborative Study Group for Micronucleus Test (CSGMT) of the Mammalian Mutagenicity Study Group (MMS) in the Japanese Environmental Mutagen Society (JEMS), the present study evaluated the effectiveness of the repeated dose liver micronucleus (RDLMN) assay. Two genotoxic hepatocarcinogens, dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF), were administered orally to male rats (6 weeks old at the initial dosing) once daily for 14 and 28 days to evaluate the micronucleus (MN) inducibility in the liver. In addition, these chemicals were evaluated for MN inducibility in the bone marrow (BM) and gastrointestinal (GI) tract, i.e. glandular stomach and colon of the same animals used in the RDLMN assay. As a result, both chemicals produced positive results in the liver, although a weak positive response was given by 2-AAF. DMN gave negative results in the tissues other than the liver. 2-AAF produced positive responses in the BM and glandular stomach, and a prominent response was particularly observed in the glandular stomach, which is directly exposed to the test chemicals by gavage. The present results suggest that the RDLMN assay is a useful method for detecting genotoxic hepatocarcinogens, and that it is especially effective for evaluating test chemicals, such as DMN, undetectable by the BM and GI tract MN assay. Moreover, the results in this investigation indicate that the use of multiple tissues in the study integrating the MN tests is more effective than using a single tissue, for detection of the MN induction produced by chemical exposure to rats, and helps to determine the characteristics of the test chemicals.

  5. Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats.

    PubMed

    Bulgheroni, Anna; Kinsner-Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar

    2009-02-01

    Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while <1% of harmful compounds were misclassified as non-toxic. Since repeated dose toxicity studies can be performed in vivo until 2013, the proposed approach could have an immediate impact for the testing of cosmetic ingredients.

  6. [Toxicity studies of landiolol hydrochloride (ONO-1101) (3). 4-week repeated dose intravenous toxicity study in dogs with 4-week recovery test].

    PubMed

    Yamaguchi, K; Yanagi, H; Shichino, Y; Shimizu, K; Ueda, H; Oida, H; Tanaka, M; Suzuki, Y; Yonezawa, H; Fujita, T

    1997-12-01

    4-week repeated dose toxicity study with 4-week recovery test of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in beagle dogs. ONO-1101 was administered intravenously to dogs of both sexes at a dose level of 0 (control), 12.5, 25 or 50 mg/kg/day. No deaths occurred throughout the treatment period. Transitory licking chops, vomiting, nausea, diarrhea and soft feces were observed occasionally in both sexes dosed 25 and 50 mg/kg/day and the incidence seemed dose-dependent. However, those incidence declined in the course of the treatment period. Hematology showed a decrease in red blood cell count, hematocrit and hemoglobin value in both sexes receiving 25 and 50 mg/kg/day. ONO-1101 did not effect on body weight, food consumption, respiratory rate, pulse, rectal temperature, heart rate, blood pressure, electrocardiography, renal or hepatic function, ophthalmology, urinalysis, occult blood in feces, blood chemistry, organ weights, necropsy and microscopic findings at any doses. These results indicate that the no-adverse-effect level of ONO-1101 in dogs is 12.5 mg/kg/day for both sexes in this study.

  7. [Toxicity studies of landiolol hydrochloride (ONO-1101) (2). 4-week repeated dose intravenous toxicity study in rats with 4-week recovery test].

    PubMed

    Yamaguchi, K; Yanagi, H; Shimizu, K; Sakai, M; Nishibata, K; Oida, H; Shinomiya, K; Suzuki, Y; Yonezawa, H; Fujita, T

    1997-12-01

    4-week repeated dose toxicity study with 4-week recovery test of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously to rats of both sexes at a dose level of 0 (control), 12.5, 25, 50 or 100 mg/kg/day. In the 100 mg/kg/day group, bradypnea or dyspnea was seen in all animals, pale in ear, eye and foot, tremor, reddish lacrimation and loss of righting reflex were also observed in some animals right after administration, and then those signs disappeared within 1 min after administration. During the treatment period, 3/20 animals of each sex in the 100 mg/kg/day showed clonic convulsion and died within 2 min after administration. No clinical changes were seen in the 50 mg/kg/day group or lower. Histopathological findings showed atrophy of the submaxillary gland in females and vessel-wall thickening and perivascular fibrosis of the injection site (tail) in both sexes at 100 mg/kg/day, however those changes were reversible. ONO-1101 did not effect on body weight, food consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weights or necropsy at any doses. These results indicate that the no-adverse-effect level of ONO-1101 in rats is 50 mg/kg/day for both sexes in this study.

  8. Repeated Dosing of 23.4% Hypertonic Saline for Refractory Intracranial Hypertension. A Case Report

    PubMed Central

    Valentino, Alden K; Nau, Karen M; Miller, David A; Hanel, Ricardo A; Freeman, WD

    2008-01-01

    Background: Hypertonic saline (HTS) at a concentration of 23.4% is an emerging therapy for intracranial hypertension. Compared to mannitol which can be given as a single bolus or as repeated bolus dosing, little data exists regarding safety or efficacy of repeated dosing of 23.4% HTS. We report the first case of 16 doses of 23.4% HTS over a 5 day period in a patient with refractory intracranial hypertension. Case Report: A 43-year-old woman with Fisher 3 subarachnoid hemorrhage and hydrocephalus requiring an external ventricular drain developed global cerebral edema on computed tomography. Medically refractory intracranial hypertension ensued which required repeated dosing of 23.4% HTS. Reductions in intracranial pressure (ICP) occurred after each dose of 23.4% HTS. No central nervous system complications occurred. Anasarca was the only observed complication, which responded to furosemide diuresis. Conclusion: Repeated dosing of 23.4% HTS was effective in reducing ICP in a case of medically refractory intracranial hypertension without major systemic complications. Prospective studies should address the safety and efficacy of repeat dose 23.4% HTS on serum sodium, intracranial pressure, and complications. PMID:22518235

  9. The relationship between overactivity and opioid use in chronic pain: a 5-day observational study.

    PubMed

    Andrews, Nicole Emma; Strong, Jenny; Meredith, Pamela Joy; Fleming, Julia Ann

    2016-02-01

    With increasing concerns about the potential harm of long-term opioid therapy, there is a need for the development and implementation of alternative treatment strategies for patients with chronic pain who have been using opioids for a prolonged period of time. Based on the findings from a recent qualitative investigation that suggested there may be a bidirectional association between opioid reliance and habitual overactivity behaviour (activity engagement that significantly exacerbates pain), this study was designed to quantitatively investigate the association between opioid use and habitual overactivity over a 5-day period in a group of chronic pain patients. Participants provided a list of their prescribed pain medication, completed a self-report measure of habitual overactivity, and then commenced 5 days of data collection. Data collection required participants to wear an activity monitor and to complete a diary that detailed their daily activities and the time at which they took medication. Individuals reporting higher levels of habitual overactivity were more likely to be prescribed opioids. In addition, higher levels of habitual overactivity were associated with more frequent pro re nata ("as needed") opioid use over the 5 days, and with a discrepancy between the prescribed and actual oral morphine-equivalent daily dose, where more medication was taken than was prescribed. There was no predominant context for pro re nata use. The results of this study support the idea that habitual overactivity behaviour may play a role in the development of reliance on opioid medication and that such an association may provide a potential treatment target for opioid therapy rationalisation.

  10. Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats.

    PubMed

    Afzan, Adlin; Abdullah, Noor Rain; Halim, Siti Zaleha; Rashid, Badrul Amini; Semail, Raja Hazlini Raja; Abdullah, Noordini; Jantan, Ibrahim; Muhammad, Hussin; Ismail, Zakiah

    2012-04-10

    Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

  11. A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers

    PubMed Central

    Cassella, James V.; Spyker, Daniel A.; Yeung, Paul P.

    2015-01-01

    Objective: This randomized, double-blind, active- and placebo-controlled, crossover, thorough QT study assessed the effect of two inhaled loxapine doses on cardiac repolarization as measured by corrected QT (QTc) interval in healthy subjects (ClinicalTrials.gov NCT01854710). Methods: Subjects received two doses of inhaled loxapine (10 mg) 2 hours apart + oral placebo, two doses of inhaled placebo + oral placebo, or two doses of inhaled placebo + oral moxifloxacin (400 mg; positive control), with ≥ 3 days washout between treatments. Two-sided 90% confidence intervals (CIs) were calculated around least-squares mean predose placebo-subtracted individually corrected QT durations (ΔΔQTcIs) at 12 time points throughout 24 hours after dosing. A ΔΔQTcI 95% upper CI exceeding 10 msec was the threshold indicating QTc prolongation (primary endpoint). Secondary endpoints included Fridericia- and Bazett-corrected QT duration and QTcI outliers. Pharmacokinetics and adverse events (AEs) were also assessed. Results: Of 60 subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post loxapine dosing, no ΔΔQTcI 95% upper CI exceeded 10 msec; the largest was 6.31 msec 5 minutes post dose 2. Methodology was validated by ΔΔQTcI 95% lower CIs exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious AEs, or AEs leading to discontinuation, and one severe AE. Conclusions: Primary and secondary endpoints indicated two therapeutic doses of inhaled loxapine did not cause threshold QTc prolongation in this study. PMID:26501204

  12. A comparative study of the repeat dose toxicity of grepafloxacin and a number of other fluoroquinolones in rats.

    PubMed

    Takizawa, T; Hasimoto, K; Itoh, N; Yamashita, S; Owen, K

    1999-01-01

    Grepafloxacin is a new oral fluoroquinolone with potent activity against community acquired respiratory pathogens, including Streptococcuspneumoniae, and pharmacokinetic properties which allow once daily dosing. As part of its safety evaluation a study of 4 weeks duration was performed to compare the toxicity of grepafloxacin with that of a number of commercially available quinolones in the rat. Groups of eight male Sprague-Dawley rats received either control material or grepafloxacin, enoxacin, lomefloxacin, ofloxacin or ciprofloxacin at an oral dosage of 300 mg/kg/day for 4 consecutive weeks. Effects related to the antibacterial activity of the drugs were seen as increased caecal weight, decreased urinary excretion of sodium, increased water consumption, decreased urine volume, increased urine osmolality, soft stools and suppressed body weight gain. It is well documented that fluoroquinolones can cause lesions in the cartilage of the major diarthrodial joints, and blister formation or erosion on the joint surface was observed in all quinolone-treated groups other than the grepafloxacin group. Some quinolones, have been found to cause crystalluria, which is often associated with secondary nephropathy in laboratory animals due to the poor solubility of quinolones under the alkaline conditions of the urine. In the present study, needle-like crystals in the urinary sediment were observed in enoxacin and ciprofloxacin treated groups only. In conclusion, grepafloxacin was well tolerated and showed a low potential for joint toxicity and crystalluria compared to other quinolones.

  13. Liver and kidney damage induced by 4-aminopyridine in a repeated dose (28 days) oral toxicity study in rats: gene expression profile of hybrid cell death.

    PubMed

    Frejo, María Teresa; Del Pino, Javier; Lobo, Margarita; García, Jimena; Capo, Miguel Andrés; Díaz, María Jesús

    2014-03-03

    4-Aminopyridine (4-AP) is an orphan drug indicated for the treatment of neuromuscular disorders. There is a great controversy around the use of this drug because of its narrow safety index and because a large number of adverse effects have been reported. Moreover, it was shown to induce cell death in different cell lines, being reported mainly apoptosis and necrosis as the principal pathways of cell death mediated by blockage of K channels or the Na, K-ATPase, but until now it was not described in vivo cell death induced by 4-aminipyridine. To provide new subchronic toxicity data and specifically, evaluate if 4-AP is able to induce in vivo cell death process and the main pathways related to it, a repeated dose (28 days) oral toxicity study, at therapeutic range of doses, was conducted in rats. The anatomical pathology, the biochemical and hematological parameters were analyzed and a real-time PCR array analysis was developed with an Ingenuity Pathway Analysis (IPA). The leucocytes number, the lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzymatic activity were increased at all dose but the erythrocytes number, the hemoglobin concentration, the alkaline phosphatase (FAL) and alanine aminotransferase (ALT) enzymatic activity were increased only at highest dose studied. However, glucose levels decreased at all doses. The biochemical results are indicative of hepatic damage. The anatomy pathology studies showed cell death only on liver and kidney, and the real-time PCR array on liver tissue expressed a gene expression profile of necrotic and apoptotic induced cell death. The present work shows for the first time in vivo cell death on liver and kidney with features of apoptosis and necrosis induced by 4-AP and the gene expression profile shows that the cell death is mediated by necrotic and apoptotic pathways that support this finding.

  14. A 4-week Repeated dose Oral Toxicity Study of Mecasin in Sprague-Dawley Rats to Determine the Appropriate Doses for a 13-week, Repeated Toxicity Test

    PubMed Central

    Cha, Eunhye; Lee, Jongchul; Lee, Seongjin; Park, Manyong; Song, Inja; Son, Ilhong; Song, Bong-Keun; Kim, Dongwoung; Lee, Jongdeok

    2015-01-01

    Objectives: In this study, we investigated the 4-week repeated-dose oral toxicity of gami-jakyak gamcho buja decoction (Mecasin) to develop safe treatments. Methods: In order to investigate the 4-week oral toxicity of Mecasin, we administered Mecasin orally to rats. Sprague-Dawley (SD) rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of Mecasin of 500, 1,000, and 2,000 mg/kg of body weight were administered to the experimental groups, and a dose of normal saline solution of 10 mL/kg was administered to the control group. We examined the survival rate, weight, clinical signs, and gross findings for four weeks. This study was conducted under the approval of the Institutional Animal Ethics Committee. Results: No deaths occurred in any of the four groups. No significant changes in weights or food consumption between the control group and the experimental groups were observed. Serum biochemistry revealed that some groups showed significant decrease in inorganic phosphorus (IP) (P < 0.05). During necropsy on the rats, one abnormal macroscopic feature, a slight loss of fur, was observed in the mid dosage (1,000 mg/ kg) male group. No abnormalities were observed in any other rats. In histopathological findings, the tubular basophilia and cast of the kidney and extramedullary hematopoiesis of the spleen were found. However, those changes were minimal and had occurred naturally or sporadically. No other organ abnormalities were observed. Conclusion: During this 4-week, repeated, oral toxicity test of Mecasin in SD rats, no toxicity changes due to Mecasin were observed in any of the male or the female rats in the high dosage group. Thus, we suggest that the doses in a 13-week, repeated test should be 0, 500, 1,000, and 2,000 mg/kg respectively. PMID:26998389

  15. Pilot study: rapidly cycling hypobaric pressure improves pain after 5 days in adiposis dolorosa

    PubMed Central

    Herbst, Karen L; Rutledge, Thomas

    2010-01-01

    Adiposis dolorosa (AD) is a rare disorder of painful nodular subcutaneous fat accompanied by fatigue, difficulty with weight loss, inflammation, increased fluid in adipose tissue (lipedema and lymphedema), and hyperalgesia. Sequential compression relieves lymphedema pain; we therefore hypothesized that whole body cyclic pneumatic hypobaric compression may relieve pain in AD. To avoid exacerbating hyperalgesia, we utilized a touch-free method, which is delivered via a high-performance altitude simulator, the Cyclic Variations in Altitude Conditioning™ (CVAC™) process. As a pilot study, 10 participants with AD completed pain and quality of life questionnaires before and after 20–40 minutes of CVAC process daily for 5 days. Participants lost weight (195.5 ± 17.6–193.8 ± 17.3 lb; P = 0.03), and bioimpedance significantly decreased (510 ± 36–490 ± 38 ohm; P = 0.01). There was a significant decrease in scores on the Pain Catastrophizing Scale (P = 0.039), in average (P = 0.002), highest (P = 0.029), lowest (P = 0.04), and current pain severity (P = 0.02) on the Visual Analogue Scale, but there was no change in pain quality by the McGill Pain Questionnaire. There were no significant changes in total and physical SF-36 scores, but the mental score improved significantly (P = 0.049). There were no changes in the Pain Disability Index or Pittsburgh Sleep Quality Index. These data present a potential, new, noninvasive means of treating pain in AD by whole body pneumatic compression as part of the CVAC process. Although randomized, controlled trials are needed to confirm these data, the CVAC process could potentially help in treating AD pain and other chronic pain disorders. PMID:21197318

  16. Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study

    PubMed Central

    García-Gea, Consuelo; Ballester, Maria Rosa; Martínez, Juan; Antonijoan, Rosa Maria; Donado, Esther; Izquierdo, Iñaki; Barbanoj, Manuel-José

    2010-01-01

    AIM The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H1-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. METHODS Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. RESULTS Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. CONCLUSION Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations. PMID:20565458

  17. A 28-day repeated dose toxicity study of ultraviolet absorber 2-(2'-hydroxy-3',5'-di-tert-butylphenyl) benzotriazole in rats.

    PubMed

    Hirata-Koizumi, Mutsuko; Watari, Nobuaki; Mukai, Daisuke; Imai, Toshio; Hirose, Akihiko; Kamata, Eiichi; Ema, Makoto

    2007-01-01

    To examine the possible repeated-dose toxicity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), CD(SD)IGS rats were administered HDBB by gavage at a dose of 0 (vehicle: corn oil), 0.5, 2.5, 12.5, or 62.5 mg kg(-1) day(-1) for 28 days. At the completion of the administration period, a decrease in red blood cells, hemoglobin, and hematocrit was noted only in males at 2.5 mg/kg and more. Blood biochemical changes were noted at 0.5 mg/kg and more in males and at 62.5 mg/kg in females. Histopathologic changes were observed principally in the liver (vacuolar degeneration and hypertrophy of hepatocytes, bile duct proliferation, etc.) and in the heart (degeneration and hypertrophy of myocardium and cell infiltration). These changes were noted at 0.5 mg/kg and more in males and at 12.5 mg/kg and more in females. At higher doses, hypertrophy of tubular epithelium in the kidneys and diffuse follicular cell hyperplasia in the thyroids in both sexes and increased severity of basophilic tubules in the kidneys and extramedullary hematopoiesis in the spleen in males were also detected. After the 14-day recovery period, these changes mostly recovered in females but not in males. Based on these findings, no observed adverse effect level (NOAEL) was concluded to be less than 0.5 mg kg(-1) day(-1) in male rats and 2.5 mg kg(-1) day(-1) in female rats.

  18. Evaluation of platelets prepared by apheresis and stored for 5 days. In vitro and in vivo studies

    SciTech Connect

    Shanwell, A.; Gulliksson, H.; Berg, B.K.; Jansson, B.A.; Svensson, L.A.

    1989-11-01

    To evaluate the effect of storage on apheresis platelets collected with a closed-system blood cell separator, an in vitro investigation was performed, with measurements of pH, lactate, ATP, the ratio of ATP to the total adenine nucleotide content, and adenylate kinase. Unmodified apheresis platelets and apheresis platelets with plasma added were compared with conventional platelets stored in PL-1240 or PL-732 plastic containers. During 6 days of storage, there were similar changes in all variables with one exception: the extracellular activity of adenylate kinase was lower in apheresis platelets with plasma than in the other three groups (p less than 0.01). In vivo studies were carried out with 111Indium-labeled autologous platelets in eight volunteers. Apheresis platelets with 100 mL of plasma added were stored in two 1000-mL containers (PL-732) at 22 degrees C during agitation. Platelets from one of the containers were labeled with 111Indium and transfused into the volunteer within 24 hours. Platelets from the other container were labeled after 5 days of storage and transfused into the same donor. There were no significant differences between apheresis platelets stored for 1 day and those stored for 5 days: the mean percentage of recovery was 58.4 and 57.6 percent, t1/2 was 69 and 67 hours, and the survival time was 5.5 and 5.6 days, respectively.

  19. Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats.

    PubMed

    Schauss, A G; Somfai-Relle, S; Financsek, I; Glavits, R; Parent, S C; Endres, J R; Varga, T; Szücs, Z; Clewell, A

    2009-01-01

    The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1000 mg/kg/day), and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1000 mg/kg/day), and blood urea nitrogen (BUN) (100 and 350, but not 1000 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result.

  20. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster.

    PubMed

    Langkilde, Søren; Mandimika, Tafadzwa; Schrøder, Malene; Meyer, Otto; Slob, Wout; Peijnenburg, Ad; Poulsen, Morten

    2009-06-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7.

  1. Safety evaluation of AB-LIFE(®) (Lactobacillus plantarum CECT 7527, 7528 and 7529): Antibiotic resistance and 90-day repeated-dose study in rats.

    PubMed

    Mukerji, Pushkor; Roper, Jason M; Stahl, Buffy; Smith, Amy B; Burns, Frank; Rae, Jessica Caverly; Yeung, Nicolas; Lyra, Anna; Svärd, Laura; Saarinen, Markku T; Alhoniemi, Esa; Ibarra, Alvin; Ouwehand, Arthur C

    2016-06-01

    AB-LIFE(®) is a probiotic product consisting of equal parts of three strains of Lactobacillus plantarum (CECT 7527, 7528, and 7529) blended with inert excipients. Whole genome sequencing was performed on each of the three strains. Antibiotic resistance was evaluated by genomic mining for resistance genes, and assessment for transferability. No risk of transfer potential was identified for any antibiotic resistance genes in the three strains. AB-LIFE(®) was evaluated for potential subchronic oral toxicity in rats, with dosages of 300 and 1000 mg/kg BW/day (equivalent to 5.55 × 10(10) and 1.85 × 10(11) CFU/kg BW/day). Survival of the three test strains through the gastrointestinal tract was supported by fecal analysis. No adverse effects were identified with respect to in-life parameters, clinical or anatomic pathology, translocation, or fecal chemical analyses. The no-observed-adverse-effect level (NOAEL) for AB-LIFE(®) in male and female rats was 1000 mg/kg BW/day (1.85 × 10(11) CFU of AB-LIFE(®)/kg BW/day), the highest dose level evaluated. These results, in conjunction with a previous acute toxicity study in rats, support the conclusion that AB-LIFE(®) is safe for human consumption.

  2. A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats.

    PubMed

    Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2014-04-01

    3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

  3. Single versus repeated doses of ivermectin and diethylcarbamazine for the treatment of Wuchereria bancrofti var. pacifica microfilaremia. Results at 12 months of a double-blind study.

    PubMed

    Cartel, J L; Spiegel, A; Nguyen Ngnoc, L; Cardines, R; Plichart, R; Martin, P M; Roux, J F

    1991-12-01

    In October 1989, 58 apparently healthy Polynesian Wuchereria bancrofti carriers in whom microfilarial (mf) density was greater than or equal to 100 mf/ml were randomly allocated to treatment groups receiving single doses of either ivermectin at 100 mcg/kg or diethylcarbamazine (DEC) at 3 and 6 mg/kg. Six months later, half of the carriers initially treated with ivermectin 100 mcg/kg or DEC 3 mg/kg were given a second similar dose while the rest were given a placebo. By day 360 (6 months after retreatment), comparison of adjusted geometric mean mf counts per group indicated that (i) among the 3 treatments given once a year the DEC 6 mg/kg dose resulted in the highest efficacy, (ii) nevertheless, regarding either ivermectin 100 mcg/kg or DEC 3 mg/kg, 2 successive doses resulted in higher efficacy than one annual dose and (iii) though no significant difference could be evidenced between efficacy of ivermectin 100 mcg/kg and DEC 3 mg/kg given twice a year, DEC seemed to sustain the mf reduction for a longer period of time. During the 3 days following retreatment, adverse reactions (mild to moderate) were observed in 46% of carriers treated with microfilaricidal drugs and in 20% of those treated with placebo. These results suggest that single dose therapy with either DEC or ivermectin is safe and effective for prevention of lymphatic filariasis due to Wuchereria bancrofti in French Polynesia. The real impact on transmission by the vector, Aedes polynesiensis, of the complete negativation of microfilaremia observed during the previous part of the trial in carriers treated with ivermectin should be evaluated in a community-based trial including entomological study.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    PubMed Central

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

  5. Evaluation of the repeated-dose liver micronucleus assay using N-nitrosomorpholine in young adult rats: report on collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study (MMS) Group.

    PubMed

    Hayashi, Aya; Kosaka, Mizuki; Kimura, Aoi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    The present study was conducted to evaluate the suitability of a repeated-dose liver micronucleus (LMN) assay in young adult rats as a collaborative study by the Mammalian mutagenicity study (MMS) group. All procedures were performed in accordance with the standard protocols of the MMS Group. Six-week-old male Crl:CD(SD) rats (5 animals/group) received oral doses of the hepatocarcinogen N-nitrosomorpholine (NMOR) at 0 (control), 5, 10, and 30mg/kg/day (10mL/kg) for 14 days. Control animals received vehicle (water). Hepatocytes were collected from the liver 24h after the last dose, and the number of micronucleated hepatocytes (MNHEPs) was determined by microscopy. The number of micronucleated immature erythrocytes (MNIMEs) in the femoral bone marrow was also determined. The liver was examined using histopathologic methods after formalin fixation. The results showed statistically significant and dose-dependent increases in the number of MNHEPs in the liver at doses of 10mg/kg and greater when compared with the vehicle control. However, no significant increase was noted in the number of MNIMEs in the bone marrow at doses of up to 30mg/kg. Histopathology of the liver revealed hypertrophy and single cell necrosis of hepatocytes at doses of 5mg/kg and above. These results showed that the induction of micronuclei by NMOR was detected by the repeated-dose LMN assay, but not by the repeated-dose bone marrow micronucleus assay.

  6. A 90-Day Oral Toxicity Study and a 5-Day Metabolism Study of Diisopropyl Methylphosphonate (DIMP) in Mink.

    DTIC Science & Technology

    1992-06-01

    Eighty 12-13 month-old brown "Ranch Wild " mink of each sex were randomized by body weight into eight dose groups of ten animals per sex. The animals...Laboratory Practice Standard (Toxic Substances Control Act) was followed. 90-DAY STUDY One hundred sixty 12-13 month-old brown "Ranch Wild " mink (80...3.2 x 10ŚM sec-’ * Hydrolysis Half- life : 687 years * Decomposition Products: (in microwave plasma discharge): methylphosphonic acid, isopropyl

  7. Repeated-dose liver micronucleus test of 4,4'-methylenedianiline using young adult rats.

    PubMed

    Sanada, Hisakazu; Koyama, Naomi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    Liver micronucleus (MN) tests using partial hepatectomized rats or juvenile rats have been shown to be useful for the detection of hepatic carcinogens. Moreover, Narumi et al. established the repeated-dose liver MN test using young adult rats for integration into general toxicity. In the present study, in order to examine the usefulness of the repeated-dose liver MN test, we investigated MN induction with a 14 or 28 day treatment protocol using young adult rats treated with 4,4′-methylenedianiline (MDA), a known hepatic carcinogen. MDA dose-dependently induced micronuclei in hepatocytes in 14- and 28-day repeated-dose tests. However, although statistically significant increases in micronuclei were observed in bone marrow cells at two dose levels in the 14-day study, there was no dose response and no increases in micronuclei in the 28-day study. These results indicate that the evaluation of genotoxic effects using hepatocytes is effective in cases where chromosomal aberrations are not clearly detectable in bone marrow cells. Moreover, the repeated-dose liver MN test allows evaluation at a dose below the maximum tolerable dose, which is required for the conventional MN test because micronucleated hepatocytes accumulate. The repeated-dose liver MN test employed in the present study can be integrated into the spectrum of general toxicity tests without further procedural modifications.

  8. Repeated dose pharmacokinetics of pancopride in human volunteers.

    PubMed

    Salva, P; Costa, J; Pérez-Campos, A; Martínez-Tobed, A

    1994-11-01

    The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL-1. The maximum plasma concentration (mean +/- SD) after the first dose was 92.5 +/- 41.5 ng ML-1 and tmax was 1.7 +/- 0.9 h. The elimination half-life (t1/2) was 14.3 +/- 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 +/- 396 ng h mL-1. The maximum plasma concentration (mean +/- SD) at steady state (day 5) was 101.8 +/- 36.9 ng mL-1 and tmax was 2.2 +/- 1.2 h. The elimination half-life (t1/2) was 16.3 +/- 2.7 h and the minimum plasma concentration (Cssmin) was 16.6 +/- 6.9 ng mL-1. The area under the concentration-time curve during the dosing interval (AUCss tau) was 995 +/- 389 ng h mL-1. The average plasma concentration at steady state (Cssav) was 43.3 +/- 16.1 ng mL-1 and the experimental accumulation ratio (RAUC) was 1.34 +/- 0.19, whereas the mean theoretical value (R) was 1.40 +/- 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Repeated-dose liver micronucleus assay: an investigation with 2-nitropropane, a hepatocarcinogen.

    PubMed

    Kawakami, Satoru; Araki, Tetsuro; Nakajima, Mikio; Kusuoka, Osamu; Uchida, Keisuke; Sato, Norihiro; Tanabe, Yoko; Takahashi, Kaori; Wako, Yumi; Kawasako, Kazufumi; Tsurui, Kazuyuki

    2015-03-01

    The utility of the repeated-dose liver micronucleus (RDLMN) assay in the detection of a genotoxic hepatocarcinogen was evaluated. In this paper, a rat hepatocarcinogen, 2-nitropropane (2-NP), was administered orally to young adult rats for 14 and 28 days without a partial hepatectomy or a mitogen, and the micronucleus induction in liver was examined using a simple method to isolate hepatocytes. In addition, a bone marrow micronucleus assay was conducted concomitantly. The frequency of micronucleated hepatocytes induced by 2-NP increased significantly in both the 14- and 28-day repeated-dose studies, while the bone marrow micronucleus assays were negative in each study. These results indicate that the RDLMN assay is useful for detecting a genotoxic hepatocarcinogen that is negative in bone marrow micronucleus assays and is a suitable in vivo genotoxicity test method for integration into a repeated-dose general toxicity study.

  10. Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).

    PubMed

    Hamada, Shuichi; Ohyama, Wakako; Takashima, Rie; Shimada, Keisuke; Matsumoto, Kazumi; Kawakami, Satoru; Uno, Fuyumi; Sui, Hajime; Shimada, Yasushi; Imamura, Tadashi; Matsumura, Shoji; Sanada, Hisakazu; Inoue, Kenji; Muto, Shigeharu; Ogawa, Izumi; Hayashi, Aya; Takayanagi, Tomomi; Ogiwara, Yosuke; Maeda, Akihisa; Okada, Emiko; Terashima, Yukari; Takasawa, Hironao; Narumi, Kazunori; Wako, Yumi; Kawasako, Kazufumi; Sano, Masaki; Ohashi, Nobuyuki; Morita, Takeshi; Kojima, Hajime; Honma, Masamitsu; Hayashi, Makoto

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.

  11. Tranexamic acid mouthwash--a prospective randomized study of a 2-day regimen vs 5-day regimen to prevent postoperative bleeding in anticoagulated patients requiring dental extractions.

    PubMed

    Carter, G; Goss, A

    2003-10-01

    This prospective randomized study analyses the use of a prescribed 4.8% tranexamic acid post-operative mouthwash over 2 days vs 5 days to prevent bleeding in patients taking warfarin who require dental extractions. Eighty-five patients therapeutically anticoagulated with warfarin for various conditions, ranging in age from 21 to 86 years and requiring dental extractions, were randomly divided into two groups. Group A postoperatively received a 4.8% tranexamic acid mouthwash to be used over a 2-day period. Group B received the same mouthwash and instructions postoperatively, to be taken over 5 days. All procedures were performed on an ambulatory basis under local anaesthetic by the same surgeon. Patients were reviewed 1, 3, and 7 days postoperatively to assess bleeding. Eighty-two of the 85 patients encountered no postoperative problems. Two patients in group A and one in group B had minor postoperative bleeds that required minor ambulatory intervention to control. This study shows that a 2-day postoperative course of a 4.8% tranexamic acid mouthwash is as equally effective as a 5-day course in controlling haemostasis post-dental extractions in patient's anticoagulated with warfarin.

  12. Comparative study of 5-day cefcapene-pivoxil and 10-day amoxicillin or cefcapene-pivoxil for treatment of group A streptococcal pharyngitis in children.

    PubMed

    Sakata, Hiroshi

    2008-06-01

    In order to compare the bacteriological and clinical efficacy and safety of cefcapene-pivoxil (CFPN-PI) for 5 days, CFPN-PI for 10 days, and amoxicillin (AMPC) for 10 days for the treatment of pharyngitis due to group A beta-hemolytic streptococcus (GAS) in children, a prospective multicenter randomized open-label comparative study was performed with 12 pediatric clinics in Asahikawa between June 2006 and February 2007. Two hundred and fifty children (age range 6 months to 12 years) with signs and symptoms of acute pharyngitis were enrolled. All had a positive throat culture for GAS and were fully evaluable. Eighty-two patients received CFPN-PI 9-10 mg/kg/day three times a day for 5 days, 88 received CFPN-PI three times a day for 10 days, and 80 received AMPC three times a day for 10 days. The CFPN-PI for 5 days regimen, the CFPN-PI for 10 days regimen, and the AMPC for 10 days regimen produced bacteriological eradication at the end of treatment in 93.8%, 96.2%, and 91.7% of the patients, respectively. The clinical cure rate observed at the end of therapy was 100% of the patients in the three groups. Relapse rates were 1.3% in CFPN-PI for 5 days, 4.0% in CFPN-PI for 10 days, and 2.9% in AMPC for 10 days. There were no significant differences in eradication rate, clinical cure rate, and relapse rate between the three treatment groups. The only adverse effects were infrequent diarrhea in all three groups, and a rash which occurred in 6 patients (8.0%) of the AMPC treatment group. Five days of treatment with CFPN-PI was as efficacious in bacteriological eradication and clinical response as 10 days of CFPN-PI or AMPC treatment.

  13. Randomized, double-blind study of short-course (5 day) grepafloxacin versus 10 day clarithromycin in patients with acute bacterial exacerbations of chronic bronchitis.

    PubMed

    Langan, C E; Zuck, P; Vogel, F; McIvor, A; Peirzchala, W; Smakal, M; Staley, H; Marr, C

    1999-10-01

    The efficacy and safety of grepafloxacin were compared with clarithromycin in a randomized, double-blind, multicentre clinical trial of 805 patients with acute bacterial exacerbations of chronic bronchitis (ABECB). Patients were randomized to receive grepafloxacin 400 mg od for either 5 (n = 273) or 10 days (n = 268) or clarithromycin 250 mg bd for 10 days (n = 261). Patients were assessed pre-treatment, 3-5 days during treatment, 1-3 days post-treatment and at follow-up (21-28 days post-treatment). The clinical success rates for the evaluable patients were 91% in the 5 day grepafloxacin group, 95% in the 10 day grepafloxacin group and 86% in the clarithromycin group. At follow-up, respective rates were 72%, 81% and 73%. A total of 513 pathogens were isolated from the pre-treatment sputum specimens of 400 (49%) patients. The primary pathogens were Haemophilus influenzae (36% of isolates), Haemophilus parainfluenzae (27%), Moraxella catarrhalis (12%), Streptococcus pneumoniae (11%) and Staphylococcus aureus (3%). Pathogens were eradicated or presumed eradicated at post-treatment in 85%, 91% and 58% of evaluable patients treated with grepafloxacin for 5 days, grepafloxacin 10 days and clarithromycin 10 days, respectively. The eradication rates in both grepafloxacin groups were significantly greater than the clarithromycin group (P<0.001). All treatments were well tolerated and incidence of drug-related adverse events in each group was comparable. This study demonstrates that both a 5 and a 10 day regimen of grepafloxacin 400 mg od are as clinically and bacteriologically effective as in the treatment of ABECB clarithromycin 250 mg bd. for 10 days.

  14. A phase I study of 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate (D-19466; lobaplatin) administered daily for 5 days.

    PubMed Central

    Gietema, J. A.; de Vries, E. G.; Sleijfer, D. T.; Willemse, P. H.; Guchelaar, H. J.; Uges, D. R.; Aulenbacher, P.; Voegeli, R.; Mulder, N. H.

    1993-01-01

    A phase I trial was conducted with lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate) i.v. bolus daily for 5 days every 4 weeks. After entering five patients toxicity appeared to be related to renal function, therefore the individual dose (total dose 20-100 mg m-2 over 5 days) of lobaplatin was modified according to creatinine clearance (CRCL) and escalated in patients. Twenty-seven patients with refractory solid tumours received 72 courses. Thrombocytopenia was dose-limiting, its degree was related to dose and CRCL at time of drug administration. With a CRCL of 60-80 ml min-1 the maximum tolerated dose was 40 mg m-2, with a CRCL of 81-100 ml min-1 70 mg m-2, and with a CRCL > 100 ml min-1 it was 85 mg m-2. Platelet and leukocyte nadirs were observed around day 21. The percentual platelet nadir (percentage of day 1 platelet count) correlated with CRCL at different dose levels and could be described by 0.76 x CRCL (ml min-1) - (1.45 x dose (mg m-2) + 43.38. This equation tested in 20 patients (28 courses) produced a correlation between observed and predicted percentual platelet nadir (r = 0.82, P < 0.001). No renal function impairment occurred. Urinary excretion of platinum (by A.A.S) was estimated in six patients and revealed that 91.5% (s.e. +/- 7.9) of the platinum dose was excreted within 4 h. Responses (one PR, one CR) occurred in two patients with ovarian cancer (both pretreated with carboplatin and cisplatin). The recommended dose of lobaplatin i.v. bolus daily for 5 days for phase II studies depends on renal function, namely 30 mg m-2 at CRCL 60-80 ml min-1; 55 mg m-2 at CRCL 81-100 ml min-1; 70 mg m-2 at CRCL > 100 ml min-1. PMID:8431374

  15. Studies of the toxicological potential of tripeptides (L-valyl-L-prolyl-L-proline and L-isoleucyl-L-prolyl-L-proline): III. Single- and/or repeated-dose toxicity of tripeptides-containing Lactobacillus helveticus-fermented milk powder and casein hydrolysate in rats.

    PubMed

    Maeno, Masafumi; Nakamura, Yasunori; Mennear, John H; Bernard, Bruce K

    2005-01-01

    The objective of these studies was to assess the toxicological potential of orally administered tripeptides in rats. The studies employed powdered L-valyl-L-prolyl-L-proline (VPP)- and L-isoleucyl-L-prolyl-L-proline (IPP)-containing test articles, including (1) powdered Lactobacillus helveticus-fermented milk (FM), (2) pasteurized casein hydrolysate (CH) generated by Aspergillus oryzae protease, and (3) synthesized VPP. All test articles were administered by oral gavage to male and female Sprague-Dawley rats. Specific goals of the single-dose and repeated-dose studies were to (1) identify doses that produce evidence of systemic and/or local (i.e., gastrointestinal) toxicity (e.g., lowest-observable-effect level [LOEL]); (2) estimate the maximally tolerated oral dose (MTD); and (3) identify specific target organs for toxicity of these tripeptides. Single doses of CH (2000 mg/kg), powdered FM (2000 or 4000 mg/kg), or VPP (40, 200, or 400 mg/kg) were administered 14 days prior to study termination. No treatment regimen caused either antemortem (gross observations, body weight, and food consumption parameters) or postmortem (necropsy) evidence of either systemic or local toxicity. In the repeated-dose study, powdered FM (0, 500, 1000, or 2000 mg/kg body weight [BW]/day) was administered by gastric gavage to male and female rats for 28 consecutive days. Antemortem evaluative parameters included gross observations, ophthalmic examinations, and clinical pathology (clinical chemistry, hematology, and urinalysis). Post mortem parameters included necropsy, determination of organ weights, and microscopic examination of major organs. There was neither in-life nor postmortem evidence that powdered FM administration caused physiological or toxicological changes. Under the conditions of these experiments, the single-dose LOEL of powdered FM, CH, and VPP were found to be greater than 4000, 2000, and 400 mg/kg, respectively. The results of the repeated-dose study do not support

  16. Evaluation of Biomarkers of Exposure in Smokers Switching to a Carbon-Heated Tobacco Product: A Controlled, Randomized, Open-Label 5-Day Exposure Study

    PubMed Central

    Haziza, Christelle; Weitkunat, Rolf; Magnette, John

    2016-01-01

    Introduction: Tobacco harm reduction aims to provide reduced risk alternatives to adult smokers who would otherwise continue smoking combustible cigarettes (CCs). This randomized, open-label, three-arm, parallel-group, single-center, short-term confinement study aimed to investigate the effects of exposure to selected harmful and potentially harmful constituents (HPHCs) of cigarette smoke in adult smokers who switched to a carbon-heated tobacco product (CHTP) compared with adult smokers who continued to smoke CCs and those who abstained from smoking for 5 days. Methods: Biomarkers of exposure to HPHCs, including nicotine and urinary excretion of mutagenic material, were measured in 24-hour urine and blood samples in 112 male and female Caucasian smokers switching from CCs to the CHTP ad libitum use. Puffing topography was assessed during product use. Results: Switching to the CHTP or smoking abstinence (SA) resulted in marked decreases from baseline to Day 5 in all biomarkers of exposure measured, including carboxyhemoglobin (43% and 55% decrease in the CHTP and SA groups, respectively). The urinary excretion of mutagenic material was also markedly decreased on Day 5 compared with baseline (89% and 87% decrease in the CHTP and SA groups, respectively). No changes in biomarkers of exposure to HPHCs or urinary mutagenic material were observed between baseline and Day 5 in the CC group. Conclusions: Our results provide clear evidence supporting a reduction in the level of exposure to HPHCs of tobacco smoke in smokers who switch to CHTP under controlled conditions, similar to that observed in SA. Implications: The reductions observed in biomarkers of exposure to HPHCs of tobacco smoke in this short-term study could potentially also reduce the incidence of cancer, cardiovascular and respiratory diseases in those smokers who switch to a heated tobacco product. PMID:26817490

  17. 14C-NaVP and 14C-PEV repeated dose study in rat. Pharmacokinetic study in rats after repeated oral administrations of 14C-valproic acid sodium salt and 14C-valproic acid pivaloyl oxymethyl ester.

    PubMed

    Bertolino, M; Acerbi, D; Canali, S; Giachetti, C; Poli, G; Ventura, P; Zanolo, G

    1998-01-01

    The absorption, excretion and tissue distribution of radioactivity after repeated oral equimolar doses of 14C-valproic acid sodium salt (NaVP) or 14C-valproic acid pivaloyl oxymethyl ester (PEV) was investigated in male rats treated once a day for 14 consecutive days. The 14th day plasma time-course of radioactivity after PEV administrations was characterised by a slow absorption rate with a delayed peak (tmax 2 h, Cmax 7.52 +/- 1.35 microg eq./ml), followed by a plateau lasting up to 8 h. After NaVP treatment, the main peak of radioactivity was observed 0.5 h after administration (Cmax 8.30 +/- 1.26 microg eq./ml) followed by a secondary peak due to biliary enterohepatic recycling. Starting from 4 h onwards, radioactivity levels after PEV treatment were higher than those after NaVP (AUCtau = 113.3 h.microg eq./ml after PEV vs 71.9 h.microg eq./ml after NaVP), but concentrations declined with similar terminal half-lives (52.8 h for PEV and 49.7 h for NaVP). Radioactivity recovered (0-432 h interval) in urine accounted for 79.3% (PEV) and 56.1% (NaVP) while, in faeces accounted for 9.1% (PEV) and 26.1% (NaVP) of total administered dose (14 days). The difference is attributable to a higher excretion of radioactivity in the bile for NaVP. The missing fraction in the total radioactivity balance is probably excreted in expired air, as observed in single dose studies. Radioactivity excreted in bile (0-8 h interval of the last 14th day) accounted for 5.1% (NaVP) and 0.23% (PEV) of the total administered dose (14 days). A possible explanation of this difference may be a different metabolism pattern for the two compounds. The negligible biliary excretion observed after PEV administration is probably due to an inhibition of the glucuronation of valproic acid (or other metabolites) caused by the pivalic acid. Due to the presence of the enterohepatic recycle, the radioactivity levels in intestine, 0.5 and 2 h after administration, were higher after NaVP administration

  18. A Whole-Genome Microarray Study of Arabidopsis thaliana Semisolid Callus Cultures Exposed to Microgravity and Nonmicrogravity Related Spaceflight Conditions for 5 Days on Board of Shenzhou 8

    PubMed Central

    Neef, Maren; Ecke, Margret; Hampp, Rüdiger

    2015-01-01

    The Simbox mission was the first joint space project between Germany and China in November 2011. Eleven-day-old Arabidopsis thaliana wild type semisolid callus cultures were integrated into fully automated plant cultivation containers and exposed to spaceflight conditions within the Simbox hardware on board of the spacecraft Shenzhou 8. The related ground experiment was conducted under similar conditions. The use of an in-flight centrifuge provided a 1 g gravitational field in space. The cells were metabolically quenched after 5 days via RNAlater injection. The impact on the Arabidopsis transcriptome was investigated by means of whole-genome gene expression analysis. The results show a major impact of nonmicrogravity related spaceflight conditions. Genes that were significantly altered in transcript abundance are mainly involved in protein phosphorylation and MAPK cascade-related signaling processes, as well as in the cellular defense and stress responses. In contrast to short-term effects of microgravity (seconds, minutes), this mission identified only minor changes after 5 days of microgravity. These concerned genes coding for proteins involved in the plastid-associated translation machinery, mitochondrial electron transport, and energy production. PMID:25654111

  19. A study of gravity-wave spectra in the troposphere and stratosphere at 5-min to 5-day periods with the Poker Flat MST radar

    NASA Technical Reports Server (NTRS)

    Bemra, R. S.; Rastogi, P. K.; Balsley, B. B.

    1986-01-01

    An analysis of frequency spectra at periods of about 5 days to 5 min from two 20-day sets of velocity measurements in the stratosphere and troposphere region obtained with the Poker Flat mesosphere-stratosphere-troposphere (MST) radar during January and June, 1984 is presented. A technique based on median filtering and averaged order statistics for automatic editing, smoothing and spectral analysis of velocity time series contaminated with spurious data points or outliers is outlined. The validity of this technique and its effects on the inferred spectral index was tested through simulation. Spectra obtained with this technique are discussed. The measured spectral indices show variability with season and height, especially across the tropopause. The discussion briefly outlines the need for obtaining better climatologies of velocity spectra and for the refinements of the existing theories to explain their behavior.

  20. Evaluation of Safety and Pharmacokinetics of Sodium 2,2 Dimethylbutyrate, a Novel Short Chain Fatty Acid Derivative, in a Phase 1, Double-Blind, Placebo-Controlled, Single- and Repeat-Dose Studies in Healthy Volunteers

    PubMed Central

    Perrine, Susan P.; Wargin, William A.; Boosalis, Michael S.; Wallis, Wayne J.; Case, Sally; Keefer, Jeffrey R.; Faller, Douglas V.; Welch, William C.; Berenson, Ronald J.

    2013-01-01

    Pharmacologic induction of fetal globin synthesis is an accepted therapeutic strategy for treatment of the beta hemoglobinopathies and thalassemias, as even small increases in hemoglobin F (HbF) levels reduce clinical severity in sickle cell disease and reduce anemia in beta thalassemia. Prior generation short chain fatty acid therapeutics, arginine butyrate and phenylbutyrate, increased fetal and total hemoglobin levels in patients, but were limited by high doses or intravenous infusion. A fetal globin-inducing therapeutic with convenient oral dosing would be an advance for these classic molecular diseases. Healthy adult human subjects were treated with a novel SCFA derivative, sodium 2,2 dimethylbutyrate (SDMB), or placebo, with one of four single dose levels (2, 5, 10 and 20 mg/kg) or daily doses (5, 10, or 15 mg/kg) over 14 days, and monitored for adverse clinical and laboratory events, drug levels, reticulocytes, and HbF assays. SDMB was well-tolerated with no clinically significant adverse events related to study medication. The terminal half-life ranged from 9–15 hours. Increases in mean absolute reticulocytes were observed at all dose levels in the 14-day study. The favorable PK profiles and safety findings indicate that SDMB warrants further investigation for treatment of anemic subjects with beta hemoglobinopathies. PMID:21422239

  1. Your Child's Development: 3-5 Days

    MedlinePlus

    ... Feeding Your 1- to 2-Year-Old Your Child’s Development: 3-5 Days KidsHealth > For Parents > Your Child’s Development: 3-5 Days A A A Though only ... the sole of the foot Social and Emotional Development soothed by a ... When to Talk to Your Doctor Every child develops at his or her own pace, but ...

  2. Your Child's Development: 3-5 Days

    MedlinePlus

    ... Feeding Your 1- to 2-Year-Old Your Child’s Development: 3-5 Days KidsHealth > For Parents > Your Child’s Development: 3-5 Days Print A A A en ... the sole of the foot Social and Emotional Development soothed by a ... When to Talk to Your Doctor Every child develops at his or her own pace, but ...

  3. The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats.

    PubMed

    Inoue, Kenji; Ochi, Akimu; Koda, Akira; Wako, Yumi; Kawasako, Kazufumi; Doi, Takaaki

    2015-03-01

    The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.

  4. Acute toxicity, twenty-eight days repeated dose toxicity and genotoxicity of vanadyl trehalose in kunming mice.

    PubMed

    Jiang, Pingzhe; Ni, Zaizhong; Wang, Bin; Ma, Baicheng; Duan, Huikun; Li, Xiaodan; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Liu, Qiqi; Xing, Shuguang; Li, Minggang

    2017-04-01

    A new trend has been developed using vanadium and organic ligands to form novel compounds in order to improve the beneficial actions and reduce the toxicity of vanadium compounds. In present study, vanadyl trehalose was explored the oral acute toxicity, 28 days repeated dose toxicity and genotoxicity in Kunming mice. The Median Lethal Dose (LD50) of vanadyl trehalose was revealed to be 1000 mg/kg body weight in fasted Kunming mice. Stomach and intestine were demonstrated to be the main target organs of vanadyl trehalose through 28 days repeated dose toxicity study. And vanadyl trehalose also showed particular genotoxicity through mouse bone marrow micronucleus and mouse sperm malformation assay. In brief, vanadyl trehalose presented certain, but finite toxicity, which may provide experimental basis for the clinical application.

  5. An abbreviated repeat dose and reproductive/developmental toxicity test for high production volume chemicals.

    PubMed

    Scala, R A; Bevan, C; Beyer, B K

    1992-08-01

    A novel protocol is described for obtaining preliminary data on repeated dose systemic effects and reproductive/developmental toxicity. The test protocol was developed by a group of experts at the request of the U.S. Environmental Protection Agency (EPA) for use as part of a Screening Information Data Set on high production volume chemicals. Interest in this protocol is shared by several regulatory agencies, including the Organization for Economic Cooperation, the European Community, and the EPA. To validate the study protocol, ethylene glycol monomethyl ether (EGME) was used. After a dosing period of approximately 6 weeks, EGME showed both systemic and reproductive/developmental effects similar to those previously reported using standard protocols. Thus, this test protocol may be used as a screening tool for high production volume chemicals.

  6. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

    PubMed

    Heard, Kennon; Bui, Alison; Mlynarchek, Sara L; Green, Jody L; Bond, G Randall; Clark, Richard F; Kozer, Eran; Koff, Raymond S; Dart, Richard C

    2014-01-01

    Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

  7. EXTRA-A Multicenter Phase II Study of Chemoradiation Using a 5 Day per Week Oral Regimen of Capecitabine and Intravenous Mitomycin C in Anal Cancer

    SciTech Connect

    Glynne-Jones, Rob Meadows, Helen; Wan, Susan; Gollins, Simon; Leslie, Martin; Levine, Ed; McDonald, Alec C.; Myint, Sun; Samuel, Les; Sebag-Montefiore, David

    2008-09-01

    Purpose: 5-Fluorouracil (5-FU) + mitomycin C (MMC)-based chemoradiotherapy is standard treatment for patients with epidermoid anal carcinoma. Clinical trials in other cancers have confirmed 5-FU can successfully be replaced by the oral fluoropyrimidine capecitabine. This phase II trial aimed to determine the feasibility, toxicity, and efficacy of capecitabine, MMC and radiotherapy (RT) in anal cancer patients. Methods and Materials: Radiotherapy comprised the schedule of the UK Anal Cancer Trial (ACT) II trial (50.4 Gy in 28 fractions of 1.8 Gy). With MMC (12 mg/m{sup 2}) on Day 1 and capecitabine on each RT treatment day in two divided doses (825 mg/m{sup 2} b.i.d). The endpoints were complete response at 4 weeks, local control at 6 months and toxicity. Results: Thirty-one patients entered the trial. The median age was 61 years (range 45-86) with 14 males and 17 females. Compliance with chemotherapy with no dose interruptions or delays was 68%, and with RT was 81%. Eighteen (58%) patients completed both modalities of treatment as planned. Dose-limiting Grade 3 or 4 diarrhea was seen in 1 of 31 patients. Three patients experienced Grade 3 neutropenia. There were no treatment-related deaths. Four weeks following completion of chemoradiation, 24 patients (77%) had a complete clinical response, and 4 (16%) a partial response. With a median follow-up of 14 months, three locoregional relapses occurred. Conclusions: Capecitabine with MMC and RT in with patients anal carcinoma is well tolerated, with minimal toxicity and acceptable compliance. We recommend testing this schedule in future national Phase III studies in anal cancer.

  8. Phase 1 study of TAS-102 administered once daily on a 5-day-per-week schedule in patients with solid tumors.

    PubMed

    Overman, Michael J; Varadhachary, Gauri; Kopetz, Scott; Thomas, Melanie B; Fukushima, Masakazu; Kuwata, Keizo; Mita, Akira; Wolff, Robert A; Hoff, Paulo M; Xiong, Henry; Abbruzzese, James L

    2008-10-01

    This study was designed to determine the safety and optimal dosing of TAS-102, a novel oral combination of alphaalphaalpha-trifluorothymidine (FTD) and an inhibitor of thymidine phoshorylase, in patients with solid tumors. Patients who met the eligibility criteria were treated with one of two different TAS-102 regimens: once per day on either days 1-5 and 8-12 every 4 weeks (schedule A) or days 1-5 every 3 weeks (schedule B). The primary objectives were the determination of the maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose. Pharmacokinetic analysis was conducted during courses 1 and 2. Sixty-three patients received a total of 172 courses of therapy with the median number of courses delivered on both schedules being 2. DLTs were observed in three patients on schedule A, 70 mg/m(2)/day (1) and 110 mg/m(2)/day (2); and in five patients on schedule B, 120 mg/m(2)/day (1), 170 mg/m(2)/day (2), 180 mg/m(2)/day (2). Granulocytopenia was the DLT in seven of the eight cases. The most frequent toxicities were nausea, fatigue, granulocytopenia, anemia, diarrhea, and abdominal pain. Twelve patients, 6 on schedule A and 6 on schedule B, were treated at the recommended phase II dose, with good tolerance. No objective responses were seen in this heavily pretreated, 5-FU-refractory population. The pharmacokinetic parameters of FTD are a T (max) of 0.53 to 3.15 h, t (1/2) of 1.46 to 4.20 h, volume of distribution of 0.0526 to 0.483 l/kg, and clearance of 0.0194 to 0.197 1/h/kg. The recommended phase II doses for TAS-102 are 100 mg/m(2)/day on schedule A and 160 mg/m(2)/day on schedule B. Future development of TAS-102 should focus upon multiple daily dosing schedules.

  9. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes

    PubMed Central

    Crowther, Caroline A; McKinlay, Christopher JD; Middleton, Philippa; Harding, Jane E

    2014-01-01

    Background It has been unclear whether repeat dose(s) of prenatal corticosteroids are beneficial. Objectives To assess the effectiveness and safety of repeat dose(s) of prenatal corticosteroids. Search methods We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (31 March 2011), searched reference lists of retrieved studies and contacted authors for further data. Selection criteria Randomised controlled trials of women who had already received a single course of corticosteroids seven or more days previously and considered still at risk of preterm birth. Data collection and analysis We assessed trial quality and extracted data independently. Main results We included 10 trials (more than 4730 women and 5650 babies) with low to moderate risk of bias. Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants experiencing the primary outcomes respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91, eight trials, 3206 infants, numbers needed to treat (NNT) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94, seven trials, 5094 infants, NNT 30, 95% CI 19 to 79). Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birthweight (mean difference (MD) −75.79 g, 95% CI −117.63 to −33.96, nine trials, 5626 infants). However, outcomes that adjusted birthweight for gestational age (birthweight Z scores, birthweight multiples of the median and small-for-gestational age) did not differ between treatment groups. At early childhood follow-up no statistically significant differences were seen for infants exposed to repeat prenatal corticosteroids compared with unexposed infants for the primary outcomes (total deaths; survival free of any disability or major disability; disability; or

  10. Toxicological assessment of refined naphthenic acids in a repeated dose/developmental toxicity screening test.

    PubMed

    McKee, Richard H; North, Colin M; Podhasky, Paula; Charlap, Jeffrey H; Kuhl, Adam

    2014-01-01

    Naphthenic acids (NAs) are primarily cycloaliphatic carboxylic acids with 10 to 16 carbons. To characterize the potential of refined NAs (>70% purity) to cause reproductive and/or developmental effects, Sprague-Dawley rats (12/group) were given oral doses of 100, 300, or 900 mg/kg/d, beginning 14 days prior to mating, then an additional 14 days for males or through lactation day 3 for females (up to 53 days) in a repeated dose/reproductive toxicity test (Organization for Economic Cooperation and Development [OECD] 422). Potential mutagenic effects were assessed using Salmonella (OECD 471) and in in vivo micronucleus tests (OECD 474) using bone marrow taken from treated animals in the screening study described previously. Systemic effects included reduced terminal body weights, increased liver weights, and changes in a number of blood cell parameters. The overall no effect level for all target organ effects was 100 mg/kg/d. In the reproductive/developmental toxicity assessment, there were significant reductions in numbers of live born offspring in groups exposed to 300 and 900 mg/kg/d. The overall no effect level for developmental effects was 100 mg/kg/d. The data from the Salmonella and micronucleus tests provide evidence that refined NAs are not genotoxic.

  11. Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma.

    PubMed

    Waters, Alicia M; Stafman, Laura L; Garner, Evan F; Mruthyunjayappa, Smitha; Stewart, Jerry E; Friedman, Gregory K; Coleman, Jennifer M; Markert, James M; Gillespie, G Yancey; Beierle, Elizabeth A

    2016-10-01

    Rhabdomyosarcoma (RMS), a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV), are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS) cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.

  12. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS).

    PubMed

    Tluczkiewicz, Inga; Batke, Monika; Kroese, Dinant; Buist, Harrie; Aldenberg, Tom; Pauné, Eduard; Grimm, Helvi; Kühne, Ralph; Schüürmann, Gerrit; Mangelsdorf, Inge; Escher, Sylvia E

    2013-11-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evaluates the conditions under which in vivo non-guideline studies are reliable. In a tiered approach three aspects of these "non-guideline" studies are assessed: the documentation of the study (reliability), the quality of the study design (adequacy) and the scope of examination (validity). The reliability is addressed by the method "Knock-out criteria", which consists of four essential criteria for repeated-dose toxicity studies. A second tool, termed QUANTOS (Quality Assessment of Non-guideline Toxicity Studies), evaluates and weights the adequacy of the study by using intra-criterion and inter-criteria weighting. Finally, the Coverage approach calculates a probability that the detected Lowest-Observed-Effect-Level (LOEL) is similar to the LOEL of a guideline study dependent on the examined targets and organs of the non-guideline study. If the validity and adequacy of the non-guideline study are insufficient for risk assessment, the ITS proposes to apply category approach or the Threshold of Toxicological Concern (TTC) concept, and only as a last resort new animal-testing.

  13. Repeated dosing with oral cocaine in humans: assessment of direct effects, withdrawal, and pharmacokinetics.

    PubMed

    Walsh, Sharon L; Stoops, William W; Moody, David E; Lin, Shen-Nan; Bigelow, George E

    2009-08-01

    Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours.

  14. Simulation for clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    PubMed

    Ishida, Kazuya; Kayano, Yuichiro; Taguchi, Masato; Hashimoto, Yukiya

    2007-11-01

    We performed a simulation for the clinical pharmacokinetic study, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral drug administration to subjects. We estimated the approximate oral clearance (CL/F(approx)) as 2.D/(C(peak).tau+C(trough).tau), where D is the dose, and tau is the dosing interval. The CL/F(approx) value was accurate for drugs with a long-elimination half-life, and the estimation error of the CL/F value was slightly increased for drugs with a shorter elimination half-life. The accuracy of CL/F(approx) in each subject was not affected by the magnitude of the interindividual pharmacokinetic variability, but was significantly decreased by the larger measurement error of drug concentrations (or intraindividual pharmacokinetic variability). We further performed several computer simulations to mimic statistical hypothesis testing following the clinical repeated-dose pharmacokinetic trials. The statistical power to detect the difference of oral clearance between two groups was marginally dependent on the measurement error of drug concentration, but was highly dependent on the interindividual pharmacokinetic variability. These findings suggested that the peak-and-trough sampling design to estimate the CL/F(approx) value is useful for clinical repeated-dose pharmacokinetic trials, and that the study design and protocol should be evaluated carefully by computer simulation prior to a real clinical trial.

  15. [Perspective of predictive toxicity assessment of in vivo repeated dose toxicity using structural activity relationship].

    PubMed

    Ono, Atsushi

    2010-01-01

    Tens of thousands of existing chemicals have been widely used for manufacture, agriculture, household and other purposes in worldwide. Only approximately 10% of chemicals have been assessed for human health hazard. The health hazard assessment of residual large number of chemicals for which little or no information of their toxicity is available is urgently needed for public health. However, the conduct of traditional toxicity tests which involves using animals for all of these chemicals would be economically impractical and ethically unacceptable. (Quantitative) Structure-Activity Relationships [(Q)SARs] are expected as method to have the potential to estimate hazards of chemicals from their structure, while reducing time, cost and animal testing currently needed. Therefore, our studies have been focused on evaluation of available (Q)SAR systems for estimating in vivo repeated toxicity on the liver. The results from our preliminary analysis showed the distribution for LogP of the chemicals which have potential to induce liver toxicity was bell-shape and indicating the possibility to estimate liver toxicity of chemicals from their physicochemical property. We have developed (Q)SAR models to in vivo liver toxicity using three commercially available systems (DEREK, ADMEWorks and MultiCASE) as well as combinatorial use of publically available chemoinformatic tools (CDK, MOSS and WEKA). Distinct data-sets of the 28-day repeated dose toxicity test of new and existing chemicals evaluated in Japan were used for model development and performance test. The results that concordances of commercial systems and public tools were almost same which below 70% may suggest currently attainable knowledge of in silico estimation of complex biological process, though it possible to obtain complementary and enhanced performance by combining predictions from different programs. In future, the combinatorial application of in silico and in vitro tests might provide more accurate

  16. Efficacy and safety profile of combination of tramadol-diclofenac versus tramadol-paracetamol in patients with acute musculoskeletal conditions, postoperative pain, and acute flare of osteoarthritis and rheumatoid arthritis: a Phase III, 5-day open-label study

    PubMed Central

    Chandanwale, Ajay S; Sundar, Subramanian; Latchoumibady, Kaliaperumal; Biswas, Swati; Gabhane, Mukesh; Naik, Manoj; Patel, Kamlesh

    2014-01-01

    Objective We aimed to evaluate the safety and efficacy of a fixed-dose combination (FDC) of tramadol and diclofenac versus a standard approved FDC of tramadol and paracetamol, in patients with acute moderate to severe pain. Methods A total of 204 patients with moderate to severe pain due to acute musculoskeletal conditions (n=52), acute flare of osteoarthritis (n=52), acute flare of rheumatoid arthritis (n=50), or postoperative pain (n=50) were enrolled in the study at baseline. Each disease category was then randomized to receive either of two treatments for 5 days: group A received an FDC of immediate-release tramadol hydrochloride (50 mg) and sustained-release diclofenac sodium (75 mg) (one tablet, twice daily), and group B received an FDC of tramadol hydrochloride (37.5 mg) and paracetamol (325 mg) (two tablets every 4–6 hours, up to a maximum of eight tablets daily). The primary efficacy end points were reductions in pain intensity from baseline at day 3 and day 5 as assessed by a Visual Analog Scale (VAS) score. Results Group A showed a significant reduction in the VAS score for overall pain from baseline on day 3 (P=0.001) and day 5 (P<0.0001) as compared with group B. The combination of tramadol-diclofenac resulted in few mild to moderate adverse events (nausea, vomiting, epigastric pain, and gastritis), which required minimal management, without any treatment discontinuation. The number of adverse events in group A was nine (8.82%) compared with 22 (21.78%) in group B, after 5 days of treatment. Conclusion An FDC of tramadol-diclofenac showed a significantly greater reduction in pain intensity and was well tolerated compared with tramadol-paracetamol, resulting in better analgesia in patients suffering from moderate to severe pain due to acute musculoskeletal conditions, postoperative pain following orthopedic surgery, or acute flare of osteoarthritis and rheumatoid arthritis. PMID:25152629

  17. Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients.

    PubMed

    Vinken, Mathieu; Pauwels, Marleen; Ates, Gamze; Vivier, Manon; Vanhaecke, Tamara; Rogiers, Vera

    2012-03-01

    Alternative methods, replacing animal testing, are urgently needed in view of the European regulatory changes in the field of cosmetic products and their ingredients. In this context, a joint research initiative called SEURAT was recently raised by the European Commission and COLIPA, representing the European cosmetics industry, with the overall goal of developing an animal-free repeated dose toxicity testing strategy for human safety assessment purposes. Although cosmetic ingredients are usually harmless for the consumer, one of the initial tasks of this research consortium included the identification of organs that could potentially be affected by cosmetic ingredients upon systemic exposure. The strategy that was followed hereof is described in the present paper and relies on the systematic evaluation, by using a self-generated electronic databank, of published reports issued by the scientific committee of DG SANCO responsible for the safety of cosmetic ingredients. By screening of the repeated dose toxicity studies present in these reports, it was found that the liver is potentially the most frequently targeted organ by cosmetic ingredients when orally administered to experimental animals, followed by the kidney and the spleen. Combined listing of altered morphological, histopathological, and biochemical parameters subsequently indicated the possible occurrence of hepatotoxicity, including steatosis and cholestasis, triggered by a limited number of cosmetic compounds. These findings are not only of relevance for the in vitro modeling efforts and choice of compounds to be tested in the SEURAT project cluster, but also demonstrate the importance of using previously generated toxicological data through an electronic databank for addressing specific questions regarding the safety evaluation of cosmetic ingredients.

  18. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates.

    PubMed

    Johnston, C C; Stremler, R; Horton, L; Friedman, A

    1999-03-01

    The purpose of this randomized clinical trial was to test the efficacy of repeated versus single dose sucrose to decrease pain from routine heel stick procedures in preterm neonates. Infants (n = 48) in the first week of life with a mean gestational age of 31 weeks received 0.05 ml of 24% sucrose solution or sterile water by mouth (1) 2 min prior to actual lancing of the heel; (2) just prior to lancing, and (3) 2 min after lancing. The single-dose group received sucrose for the first dose and water for the second and third dose; the repeated-dose group received sucrose three times, and the placebo group received only water. The Premature Infant Pain Profile (PIPP) scores were obtained for five 30-second blocks from lancing. Both sucrose groups had lower PIPP scores (single sucrose pain scores, 6.8-8.2, p = 0.07; repeated sucrose pain scores, 5.3-6. 2, p < 0.01) than water (pain scores 7.9-9.1), and in the last block, the repeated dose had lower scores than the single dose (6.2 vs. 8. 2, p < 0.05).

  19. Inhalation exposure system used for acute and repeated-dose methyl isocyanate exposures of laboratory animals.

    PubMed

    Adkins, B; O'Connor, R W; Dement, J M

    1987-06-01

    Laboratory animals were exposed by inhalation for 2 hr/day (acute) or 6 hr/day (four consecutive days, repeated dose) to methyl isocyanate (MIC). Exposures were conducted in stainless steel and glass inhalation exposure chambers placed in stainless steel, wire mesh cages. MIC was delivered with nitrogen via stainless steel and Teflon supply lines. Chamber concentrations ranged from 0 to 60 ppm and were monitored continuously with infrared spectrophotometers to 1 ppm and at 2-hr intervals to 20 ppb with a high performance liquid chromatograph equipped with a fluorescence detector. Other operational parameters monitored on a continuous basis included chamber temperature (20-27 degrees C), relative humidity (31-64%), static (transmural) pressure (-0.3 in.), and flow (300-500 L/min). The computer-assistance system interfaced with the inhalation exposure laboratory is described in detail, including the analytical instrumentation calibration system used throughout this investigation.

  20. Pharmacokinetics of grepafloxacin after oral administration of single and repeat doses in healthy young males.

    PubMed

    Efthymiopoulos, C; Bramer, S L; Maroli, A

    1997-01-01

    The pharmacokinetics of grepafloxacin in healthy male subjects following single oral administration of doses ranging from 200 to 1200 mg, and following repeated oral administration of 400 and 800 mg doses are reported. Plasma levels of grepafloxacin reached a peak within 2 hours (on average) following drug administration and then declined bi-exponentially with concentrations being detectable (> 5 micrograms/L) in the plasma for at least up to 72 hours postdose. The high values for the apparent volume of distribution (5 to 8 L/kg) suggested extensive distribution of grepafloxacin in the tissues. Only a small percentage of the administered dose (ranging from 6% to 9.5%) was recovered in the urine as unchanged grepafloxacin, suggesting that metabolism, rather than urinary excretion, is the major elimination route. The half-life of grepafloxacin was about 12 hours after single doses and about 15 hours after repeat doses. The trough levels increased significantly over the first 3 days of repeat administration; thereafter, the changes were small, with steady-state being reached by the fifth day. The area under the concentration-time curve (AUC24 h) values observed on days 7 and 14 of repeat administration, at each dose level, were similar, suggesting that steady-state is maintained. The area values increased more than proportionally after administration of increasing single and repeat doses, suggesting nonlinear kinetics. The elimination half-life and renal clearance did not change with increasing doses. Saturation in the metabolism of grepafloxacin and possibly in the distribution into a peripheral compartment, as suggested by a decrease in the total plasma clearance and in the apparent volume of distribution, could be the origin of the nonlinear kinetics. However, this deviation from linearity is unlikely to be of clinical significance, since it was very small over the recommended range of therapeutic doses (400 to 600 mg once daily). Compared with other quinolones

  1. Safety and Pharmacokinetics of Repeat-Dose Micafungin in Young Infants

    PubMed Central

    Benjamin, Daniel K; Smith, P Brian; Arrieta, Antonio; Castro, Lisa; Sánchez, Pablo J; Kaufman, David; Arnold, Leah J; Kovanda, Laura L; Sawamoto, Taiji; Buell, Donald N; Hope, William W; Walsh, Thomas J

    2010-01-01

    Due to the risk of central nervous system infection, relatively high weight-based echinocandin dosages may be required for successful treatment of invasive candidiasis and candidemia in young infants. This open-label study assessed safety and pharmacokinetics of micafungin in 13 young infants (> 48 hours of age and < 120 days of life) with suspected candidemia or invasive candidiasis. Infants weighing ≥ 1,000 g and < 1,000 g received 7 and 10 mg/kg/day, respectively, for a minimum of 4 to 5 days. Mean baseline weight and gestational age were 2101 g and 688 g, and 30 weeks and 25 weeks, in the 7 and 10 mg/kg/day groups, respectively. Median pharmacokinetic values for the 7 and 10 mg/kg/day groups, respectively, were: AUC0–24, 258.1 and 291.2 μg•h/ml; Clss/wt, 0.45 and 0.57 ml/min/kg; Cmax, 23.3 and 24.9 μg/ml; and Vdss/wt, 341.4 and 542.8 ml/kg. No deaths or discontinuations from treatment occurred. These data suggest that micafungin dosages of 7 and 10 mg/kg/day were well tolerated and provided exposure that was demonstrated in animal model to be adequate for central nervous system coverage. PMID:19890251

  2. NASA Animation Shows Hurricane Otto Over 5 Days

    NASA Video Gallery

    A 5-day movie of NOAA's GOES-East satellite infrared and visible imagery of Hurricane Otto was created by the NASA/NOAA GOES Project at NASA's Goddard Space Flight Center in Greenbelt, Maryland. Th...

  3. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

    PubMed

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi

    2014-06-01

    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.

  4. Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure.

    PubMed

    Fabian, E; Bordag, N; Herold, M; Kamp, H; Krennrich, G; Looser, R; Ma-Hock, L; Mellert, W; Montoya, G; Peter, E; Prokudin, A; Spitzer, M; Strauss, V; Walk, T; Zbranek, R; van Ravenzwaay, B

    2016-07-25

    The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.

  5. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1) Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  6. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1)Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  7. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1) Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  8. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1)Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  9. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1)Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  10. Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

    PubMed Central

    Guo, RX; Anaclet, C; Roberts, JC; Parmentier, R; Zhang, M; Guidon, G; Buda, C; Sastre, JP; Feng, JQ; Franco, P; Brown, SH; Upton, N; Medhurst, AD; Lin, JS

    2009-01-01

    Background and purpose: Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously. Experimental approach: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep–wake cycle in wild-type (Ox+/+) and orexin knockout (Ox−/−) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography. Key results: In Ox+/+ and Ox−/− mice, acute administration of GSK189254 (3 and 10 mg·kg−1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg−1), while it reduced narcoleptic episodes in Ox−/− mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·kg−1) on W in both Ox+/+ and Ox−/− mice was significantly reduced, while the effect on narcoleptic episodes in Ox−/− mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox−/− mice. Conclusions and implications: These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies. PMID:19413575

  11. The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

    PubMed

    Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

    2013-01-01

    The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds.

  12. An Uncontrolled Examination of a 5-Day Intensive Treatment for Pediatric OCD

    ERIC Educational Resources Information Center

    Whiteside, Stephen P.; Jacobsen, Amy Brown

    2010-01-01

    This study examined the feasibility of a 5-day intensive treatment for pediatric obsessive-compulsive disorder (OCD). Fifteen children with OCD received a week-long treatment based on exposure and response prevention (ERP). The intervention also emphasized teaching children and parents how to conduct ERP independently at home. All families…

  13. Zonal Wave Number 2 Rossby Wave (3.5-day oscillation) Over The Martian Lower Atmosphere

    NASA Astrophysics Data System (ADS)

    Ghosh, P.; Thokuluwa, R. K.

    2013-12-01

    Over the Mars, height (800-50 Pascal pressure coordinate) profiles of temperature (K), measured by radio occultation technique during the MGS (Mars Global Surveyor) mission, obtained for the period of 1-10 January 2006 at the Martian latitude of ~63N in almost all the longitudes are analyzed to study the characteristics of the 3.5-day oscillation. To avoid significant data gaps in a particular longitude sector, we selected a set of 7 Mars longitude regions with ranges of 0-30E, 35-60E, 65-95E, 190-230E, 250-280E, 290-320E, and 325-360E to study the global characteristics of the 3.5-day oscillation. The 3.5-day oscillation is not selected as a-priori but observed as a most significant oscillation during this period of 1-10 January 2006. It is observed that in the longitude of 0-30E, the 3.5-day oscillation shows statistically significant power (above the 95% confidence level white noise) from the lowest height (800 Pascal, 8 hPa) itself and up to the height of 450 Pascal level with the maximum power of ~130 K^2 at the 600 & 650 Pascal levels. It started to grow from the power of ~ 50 K^2 at the lowest height of 800 Pascal level and reached the maximum power in the height of 600-650 Pascal level and then it started to get lessened monotonously up to the height of 450 Pascal level where its power is ~ 20 K^2. Beyond this height and up to the height of 50 Pascal level, the wave amplitude is below the white noise level. As the phase of the wave is almost constant at all the height levels, it seems that the observed 3.5-day oscillation is a stationary wave with respect to the height. In the 35-60 E longitude sector, the vertical structure of the 3.5-day oscillation is similar to what observed for the 0-30 E longitude region but the power is statistically insignificant at all the heights. However in the 65-95E longitude sector, the wave grows from the lowest level (70 K^2) of 800 Pascal to its maximum power of 280 K^2 in the height of 700 Pascal level and then it started

  14. Evaluation of in vivo genotoxicity by thioacetamide in a 28-day repeated-dose liver micronucleus assay using male young adult rats.

    PubMed

    Sui, Hajime; Matsumoto, Hirotaka; Wako, Yumi; Kawasako, Kazufumi

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens and can be integrated into general toxicological studies. In this study, thioacetamide (TAA) was tested in 14- and 28-day RDLMN assays to assess the performance of the assay. The test substance, TAA, was administered orally to 6-week-old male Crl:CD (SD) rats once daily for 14 or 28 days at a dosage of 5, 10 or 20mg/kg/day. Hepatocytes were collected approximately 24h after the last TAA administration, and the incidence of micronuclei was assessed. In this study, bone marrow micronucleus assays were also conducted in the same animals. The 14- and 28-day RDLMN assays indicated that none of the TAA dosages significantly increased the proportion of micronucleated hepatocytes. Bone marrow micronucleus assays with TAA also provided negative results. It is known that TAA is a liver carcinogen in mice and rats. In the previous genotoxic studies, the Ames test and the chromosomal aberration test using CHL/IU cells have yielded negative results [1-4]. The liver micronucleus assay using young adult rats singly dosed with TAA (75 and 150mg/kg) also produced negative results [5]. TAA gave positive results only in the mouse bone marrow micronucleus assays [6,7].

  15. Additional notes on clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    PubMed

    Takaai, Mari; Kayano, Yuichiro; Shimizu, Takako; Taguchi, Masato; Hashimoto, Yukiya

    2008-01-01

    In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral administration at the dose, D, and dosing interval, tau. The approximate oral clearance (CL/F(approx)), estimated as 2 x D/(C(peak) x tau+C(trough) x tau), is accurate for drugs with an elimination half-life comparative to or longer than tau; however, it was suggested that we might not use CL/F(approx) for drugs with a considerably short elimination half-life relative to tau. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F(exp)) estimated by the simple monoexponential model. In contrast to CL/F(approx), CL/F(exp) was accurate for drugs with a short elimination half-life relative to tau. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F(approx) and CL/F(exp)) for a target drug should be evaluated carefully before and after a real clinical trial.

  16. Prospective evaluation of potential toxicity of repeated doses of Thymus vulgaris L. extracts in rats by means of clinical chemistry, histopathology and NMR-based metabonomic approach.

    PubMed

    Benourad, Fouzia; Kahvecioglu, Zehra; Youcef-Benkada, Mokhtar; Colet, Jean-Marie

    2014-10-01

    In the field of natural extracts, research generally focuses on the study of their biological activities for food, cosmetic, or pharmacological purposes. The evaluation of their adverse effects is often overlooked. In this study, the extracts of Thymus vulgaris L. were obtained by two different extraction methods. Intraperitoneal injections of both extracts were given daily for four days to male Wistar Han rats, at two different doses for each extract. The evaluation of the potential toxic effects included histopathological examination of liver, kidney, and lung tissues, as well as serum biochemistry of liver and kidney parameters, and (1)H-NMR-based metabonomic profiles of urine. The results showed that no histopathological changes were observed in the liver and kidney in rats treated with both extracts of thyme. Serum biochemical investigations revealed significant increases in blood urea nitrogen, creatinine, and uric acid in animals treated with polyphenolic extract at both doses. In these latter groups, metabonomic analysis revealed alterations in a number of urine metabolites involved in the energy metabolism in liver mitochondria. Indeed, the results showed alterations of glycolysis, Krebs cycle, and β-oxidative pathways as evidenced by increases in lactate and ketone bodies, and decreases in citrate, α-ketoglutarate, creatinine, hippurate, dimethylglycine, and dimethyalanine. In conclusion, this work showed that i.p. injection of repeated doses of thyme extracts causes some disturbances of intermediary metabolism in rats. The metabonomic study revealed interesting data which could be further used to determine the cellular pathways affected by such treatments.

  17. Clinical and pathological effects of short-term cyanide repeated dosing to goats.

    PubMed

    Soto-Blanco, B; Stegelmeier, B L; Górniak, S L

    2005-01-01

    The purpose of this work is to determine and describe the effects of subacute cyanide toxicity to goats. Eight female goats were divided into two groups. The first group of five animals was treated with 8.0 mg KCN kg(-1) body weight day(-1) for seven consecutive days. The second group of three animals was treated with water as controls. Complete physical examination, including observation for behavior changes, was conducted before and after dosing. One treated animal was euthanized immediately after dosing. Later, two of the remaining treated animals and a control goat were euthanized after a 30-day recovery period. Euthanized animals were necropsied and tissues were collected and prepared for histologic studies. Clinical signs in treated goats were transient and included depression and lethargy, mild hyperpnea and hyperthermia, arrhythmias, abundant salivation, vocalizations, expiratory dyspnea, jerky movements and head pressing. Two goats developed convulsions after day 3 of treatment. One animal developed more permanent behavioral changes as she became less dominant and aggressive. Histologic changes included mild hepatocellular vacuolation and degeneration, mild vacuolation and swelling of the proximal convoluted tubules of the kidneys and spongiosis of the white matter (status spongiosis) of the cerebral white tracts, internal capsule, cerebellar peduncles, spinal cord and peripheral nerves. In summary, sub-lethal cyanide intoxication in goats resulted in behavioral changes, and during the treatment period animals showed delayed signs of toxicity. Significant histologic lesions in goats were observed and need to be characterized further.

  18. A 13-week repeated-dose oral toxicity and bioaccumulation of aluminum oxide nanoparticles in mice.

    PubMed

    Park, Eun-Jung; Sim, Jaehoon; Kim, Younghun; Han, Beom Seok; Yoon, Cheolho; Lee, Somin; Cho, Myung-Haing; Lee, Byoung-Seok; Kim, Jae-Ho

    2015-03-01

    Because of an increase in the commercial applications of manufactured nanoparticles, the issue of potential adverse health effects of nanoparticles following intended or unintended exposure is rapidly gaining attention. In this study, we evaluated the toxicity of aluminum oxide nanoparticles (AlNPs, rod-type, 1.5, 3, and 6 mg/kg) after oral administration to mice for 13 weeks. Compared with the control group, the consumption of diet and drinking water and body weight gain decreased in the group treated with AlNPs. The group treated with 6 mg/kg AlNPs also showed a marked elevation in the count of white blood cells that associated with a significant decrease and increase to the proportion of eosinophils and lymphocytes, respectively. In addition, the secretion of IL-6 and monocyte chemotactic protein-1 increased in a dose-dependent manner in the treated groups. Furthermore, AlNPs showed the highest accumulation in the liver and kidneys compared with the control group, increased the lactate dehydrogenase level in the blood, and induced the development of a pathological lesion in the liver and kidneys. Taken together, we suggest that the target organs of rod-type AlNPs may be the liver, kidneys and the immune system, and the not-observed adverse effect level may be lower than 6 mg/kg.

  19. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease.

    PubMed

    Ferruzzi, Mario G; Lobo, Jessica K; Janle, Elsa M; Cooper, Bruce; Simon, James E; Wu, Qing-Li; Welch, Cara; Ho, Lap; Weaver, Connie; Pasinetti, Giulio M

    2009-01-01

    The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 +/-45.9 and 576.7 +/- 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.

  20. Single- and repeat-dose toxicity of IDX14184, a nucleotide prodrug with antiviral activity for hepatitis C viral infection, in mice, rats, and monkeys.

    PubMed

    Luo, S; Rush, R; Standring, D

    2016-05-01

    The single- and repeat-dose toxicity profile of IDX14184, a novel guanosine nucleotide prodrug with antiviral activity against hepatitis C viral infection, was characterized following once daily oral administration for durations up to 13, 26, and 32 weeks in mouse, rat, and cynomolgus monkey, respectively. The heart, liver, kidney, skeletal muscles, and lower gastrointestinal tract (cecum, colon, and/or rectum) were identified as the primary toxicity targets in these nonclinical species. The mouse was relatively insensitive to IDX14184-induced cardiac toxicity and hepatotoxicity. The rat was very sensitive to IDX14184-induced skeletal muscle, liver, heart, and lower gastrointestinal tract toxicity but relatively insensitive to kidney toxicity. The monkey is a good animal species to detect IDX14184-induced toxicity in the cardiac and skeletal muscles, and in the liver and kidney, but not lower gastrointestinal tract toxicity. The toxicity profile of IDX14184 was most appropriately characterized in rats and monkeys. The conduct of a series of cardiac size and function assessments during a non-rodent toxicology study using echocardiography proved great utility in this work. IDX14184 clinical development was eventually terminated due to suboptimal efficacy and regulatory concerns on potential heart and kidney injury in patients, as seen with a different guanosine nucleotide prodrug, BMS-986094.

  1. Toxicity profile of repeated doses of PEG-asparaginase incorporated into a pediatric-type regimen for adult acute lymphoblastic leukemia.

    PubMed

    Aldoss, Ibrahim; Douer, Dan; Behrendt, Carolyn E; Chaudhary, Preeti; Mohrbacher, Ann; Vrona, Janice; Pullarkat, Vinod

    2016-04-01

    Despite having been long regarded as too toxic for adult patients, pediatric-like regimens containing L-asparaginase have resulted in improved outcomes for adults with acute lymphoblastic leukemia (ALL). To characterize the spectrum of toxicity of repeated doses of polyethylene glycolated-asparaginase (PEG-asp) in adults, we reviewed all doses (2000 IU/m(2) ) administered as part of a pediatric-inspired regimen in adult ALL at our center. Subjects aged 18-60 yr with ALL (n = 152, 69.1% male) contributed 522 dose cycles to the study. Hepatotoxicity was the most common adverse event: grades 3-4 transaminitis and hyperbilirubinemia occurred in 53.9% and 23.7% of subjects, respectively. Hepatotoxicity was reversible; no cases of fulminate hepatic failure were observed. Other toxicities affecting at least 5% of subjects were grades 3-4 triglyceridemia in 50.9%, hypofibrinogenemia (<100 mg/dL) in 47.9%, clinical pancreatitis in 12.6%, venous thromboembolism in 11.2%, allergic reaction in 7.2%, and any grade bleeding in 5.3%. PEG-asp was always discontinued after grades 3-4 pancreatitis or allergic reaction. Otherwise, toxicities did not preclude administration of additional cycles of the drug. Our results suggest that repeated PEG-asp dosing is safe in adults aged 18-60 yr, even after occurrence of a drug-related toxicity.

  2. Corn rootworm-active RNA DvSnf7: Repeat dose oral toxicology assessment in support of human and mammalian safety.

    PubMed

    Petrick, Jay S; Frierdich, Gregory E; Carleton, Stephanie M; Kessenich, Colton R; Silvanovich, Andre; Zhang, Yuanji; Koch, Michael S

    2016-11-01

    Genetically modified (GM) crops have been developed and commercialized that utilize double stranded RNAs (dsRNA) to suppress a target gene(s), producing virus resistance, nutritional and quality traits. MON 87411 is a GM maize variety that leverages dsRNAs to selectively control corn rootworm through production of a 240 base pair (bp) dsRNA fragment targeting for suppression the western corn rootworm (Diabrotica virgifera virgifera) Snf7 gene (DvSnf7). A bioinformatics assessment found that endogenous corn small RNAs matched ∼450 to 2300 unique RNA transcripts that likely code for proteins in rat, mouse, and human, demonstrating safe dsRNA consumption by mammals. Mice were administered DvSnf7 RNA (968 nucleotides, including the 240 bp DvSnf7 dsRNA) at 1, 10, or 100 mg/kg by oral gavage in a 28-day repeat dose toxicity study. No treatment-related effects were observed in body weights, food consumption, clinical observations, clinical chemistry, hematology, gross pathology, or histopathology endpoints. Therefore, the No Observed Adverse Effect Level (NOAEL) for DvSnf7 RNA was 100 mg/kg, the highest dose tested. These results demonstrate that dsRNA for insect control does not produce adverse health effects in mammals at oral doses millions to billions of times higher than anticipated human exposures and therefore poses negligible risk to mammals.

  3. Combined repeated dose and reproductive/developmental toxicity screening test of the nitrophenolic herbicide dinoseb, 2-sec-butyl-4,6-dinitrophenol, in rats.

    PubMed

    Matsumoto, Mariko; Furuhashi, Tadakazu; Poncipe, Carlo; Ema, Makoto

    2008-04-01

    In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, Crj:CD(SD)IGS rats were dosed with dinoseb, 2-sec-butyl-4,6-dinitrophenol, by gavage at 0 (vehicle), 0.78, 2.33, or 7.0 mg/kg bw/day. Six males per group were dosed for a total of 42 days beginning 14 days before mating. Twelve females per group were dosed for a total of 44-48 days beginning 14 days before mating to day 6 of lactation throughout the mating and gestation period. Recovery groups of six males per group and nonpregnant six females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in males of any dose group or in females of the recovery groups. At 7.0 mg/kg bw/day, eight females died and two animals were moribund during late pregnancy, and a significant decrease in body weight gain was found in both sexes. Hematocrit was significantly higher at 0.78 mg/kg bw/day and above in the main group males at the end of administration period. Reduction in extramedullary hematopoiesis in the spleen was significant at 2.33 mg/kg bw/day in the main group females. Sperm analysis revealed a decrease in sperm motility and an increase in the rates of abnormal sperm, abnormal tail, and abnormal head at 7.0 mg/kg bw/day. A number of dams delivered their pups and of dams with live pups at delivery was significantly lowered in the 7.0 mg/kg bw/day group. Based on these findings, the LOAEL for males and NOAEL for females were 0.78 mg/kg bw/day, and the NOAEL for reproductive/developmental toxicity was considered to be 2.33 mg/kg bw/day.

  4. Administration of hCG 5 days after breeding and reproductive performance in nulliparous dairy goats.

    PubMed

    Fonseca, J F; Torres, C A A

    2005-12-01

    The objective of this study was to investigate the effect of hCG administration 5 days after breeding on plasma progesterone (P4) concentration and reproductive performance of oestrous-induced nulliparous dairy goats. A total of 59 nulliparous goats (36 Alpine and 23 Saanen) received intravaginal sponges with 60 mg medroxyprogesterone acetate for 9 days plus 200 IU equine chorionic gonadotrophin (eCG) and 22.5 microg d-cloprostenol 24 h before sponge removal. After detection of oestrus (day of oestrus = day 0) and breeding, 49 females were randomly assigned, according to the breed, into two treatments (T1 and T2). In T1 (n = 25) and T2 (n = 24), animals received intramuscular injection of 1 ml of saline solution (control) or 250 IU hCG, respectively, 5 days after breeding. Plasma P4 concentration (ng/ml) was determined from blood sampled on days 0, 5, 7, 13, 17, 21, 28 and 45 after breeding. Animals were scanned by transrectal ultrasound (5 MHz probe) on days 35 and 70 after breeding for detection of pregnancy. Plasma P4 concentration did not differ (p > 0.05) between treatments in all days, but it was increased (p < 0.05) in Saanen than in Alpine goats from days 13 to 45. Pregnancy and parturition rates, litter size and gestation period were similar (p > 0.05) to treatments and breeds. Results of this study indicate that human chorionic gonadotrophin (hCG) administration 5 days after breeding did not significantly alter reproductive performance in dairy nulliparous goats and that plasma P4 differed between Saanen and Alpine goats.

  5. Does the adolescent patellar tendon respond to 5 days of cumulative load during a volleyball tournament?

    PubMed

    van Ark, M; Docking, S I; van den Akker-Scheek, I; Rudavsky, A; Rio, E; Zwerver, J; Cook, J L

    2016-02-01

    Patellar tendinopathy (jumper's knee) has a high prevalence in jumping athletes. Excessive load on the patellar tendon through high volumes of training and competition is an important risk factor. Structural changes in the tendon are related to a higher risk of developing patellar tendinopathy. The critical tendon load that affects tendon structure is unknown. The aim of this study was to investigate patellar tendon structure on each day of a 5-day volleyball tournament in an adolescent population (16-18 years). The right patellar tendon of 41 players in the Australian Volleyball Schools Cup was scanned with ultrasound tissue characterization (UTC) on every day of the tournament (Monday to Friday). UTC can quantify structure of a tendon into four echo types based on the stability of the echo pattern. Generalized estimating equations (GEE) were used to test for change of echo type I and II over the tournament days. Participants played between eight and nine matches during the tournament. GEE analysis showed no significant change of echo type percentages of echo type I (Wald chi-square = 4.603, d.f. = 4, P = 0.331) and echo type II (Wald chi-square = 6.070, d.f. = 4, P = 0.194) over time. This study shows that patellar tendon structure of 16-18-year-old volleyball players is not affected during 5 days of cumulative loading during a volleyball tournament.

  6. [Antibacterial activity of urine after administration of ofloxacin for 5 days].

    PubMed

    Drugeon, H; Veyries, M L; Levacher, M; Garnier, M; Aymard, G; Giroud, J P; Rouveix, B

    2000-01-01

    The antibacterial activity of ofloxacin was evaluated in urine over a period of 96 h after oral administration for 5 days of 200 mg twice a day in 12 healthy female volunteers. Bacteriostatic and bactericidal activity of urines were studied for five strains of enterobacterias recovered from urinary infections: two strains of Escherichia Coli Nal-S and Nal-R, two strains of Proteus mirabilis Nal-S and Nal-R, and one strain of Klebsiella pneumoniae Nal-S. Mean urinary concentrations of ofloxacin were very high during the first 12 h following last intake. They were still above 7 mg/l till the 48th hour and above 1.6 mg/l till the 72nd hour. Bactericidal activity of urine was present for 72 h in respect of four strains studied at that time; urine was not bactericidal as regards E. coli Nal-R. After 5 days of oral treatment with ofloxacin (200 mg b.i.d.), urine retains a bactericidal activity for at least 72 h against bacterial strains of urinary tract infections.

  7. Evaluation of 5-day therapy with telithromycin, a novel ketolide antibacterial, for the treatment of tonsillopharyngitis.

    PubMed

    Norrby, S R; Quinn, J; Rangaraju, M; Leroy, B

    2004-07-01

    A pooled analysis of two double-blind, multicentre, Phase III studies compared oral telithromycin 800 mg once-daily for 5 days with penicillin V 500 mg three-times-daily or clarithromycin 250 mg twice-daily for 10 days in the treatment of Streptococcus pyogenes (group A beta-haemolytic streptococcus; GABHS) tonsillopharyngitis. Patients aged > or = 13 years with acute GABHS tonsillopharyngitis were randomised to receive telithromycin (n = 430), penicillin (n = 197) or clarithromycin (n = 231). Clinical isolates of S. pyogenes (n = 590) obtained from throat swab samples on study entry were tested for their in-vitro susceptibility to telithromycin, clarithromycin and azithromycin. Telithromycin demonstrated in-vitro activity against the clinical isolates of S. pyogenes (MIC50/90 0.03/0.06 mg/L) higher than clarithromycin or azithromycin (MIC50/90 0.06/0.06 mg/L and 0.12/0.25 mg/L, respectively), including erythromycin-resistant strains. At the post-therapy/test of cure (TOC) visit (days 16-23), satisfactory bacteriological outcome was demonstrated for 88.3% (234/265) and 88.6% (225/254) of telithromycin- and comparator-treated patients, respectively (per-protocol population). Overall, GABHS eradication rates were 88.7% (235/265) for telithromycin and 89.0% (226/254) for comparators. The clinical cure rates at the post-therapy/TOC visit were 93.6% (248/265) and 90.9% (220/242) for telithromycin and pooled comparators, respectively. Telithromycin was generally well-tolerated. Most adverse events considered to be possibly related to study medication were gastrointestinal and of mild intensity. Discontinuations as a result of adverse events were few in both treatment groups. In conclusion, telithromycin 800 mg once-daily for 5 days was as effective as penicillin V or clarithromycin for 10 days in the treatment of GABHS tonsillopharyngitis.

  8. [Dynamics of the protein content of human urine during 5-day immersion].

    PubMed

    Vorontsov, A L; Nesterovskaia, A Iu; Morukov, B L; Markin, A A; Zhuravleva, O A; Zabolotskaia, I V; Vostrikova, L V

    2011-01-01

    Variations in the protein spectrum (12 groups) of native daily urine were studied during 5-day dry immersion (DI) of 14 subjects at the age of 19 to 26 years using gradient electrophoresis in polyacrylamide gel. Protein excretion with urine did not alter in the course of the experiment. However, the urine proteins spectrum trended to some shifts. Excretion of low-molecular proteins decreased and of albumin increased pointing to remodulation of tubular reabsorption initiated by the experimental conditions. Steady growth of the Tamm-Horsfall protein concentration seems to be a defense reaction. There was an incremental decrease in immunoglobulins that could be associated with a reduction of glomerular filter permeability for high-molecular proteins.

  9. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

    PubMed

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

    2015-04-01

    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

  10. Continuing Assessment of the 5-Day Sodium Carbonate-Ammonium Nitrate Extraction Assay as an Indicator Test for Silicon Fertilizers.

    PubMed

    Zellner, Wendy; Friedrich, Russell L; Kim, Sujin; Sturtz, Douglas; Frantz, Jonathan; Altland, James; Krause, Charles

    2015-01-01

    The 5-day sodium carbonate-ammonium nitrate extraction assay (5-day method) has been recognized by the American Association of Plant Food Control Officials as a validated test method to identify fertilizers or beneficial substances that provide plant-available silicon (Si). The test method used the molybdenum blue colorimetric assay to quantify percentage Si; however, laboratories may use inductively coupled plasma optical emission spectroscopy (ICP-OES) for elemental analysis. To examine the use of either colorimetric or ICP-OES methods for Si determination, the 5-day method was performed on the following Si-containing compounds; wollastonite, sand, biochar, and a basic oven furnace (BOF) slag. Grow-out studies using Zinnia elegans were also performed using varying rates of the wollastonite, biochar, and BOF slag. Our results show using the 5-day method, wollastonite had the highest extracted amounts of silicic acid (H4SiO4) at 4% followed by biochar (2%), BOF slag (1%), and sand (0%). Extraction values calculated using either the molybdenum blue colorimetric assay or ICP-OES for detection of the H4SiO4 had a significant correlation, supporting the application of either detection method for this type of analysis. However, when extracted values were compared to amounts of Si taken up by the plants, the 5-day method overestimated both wollastonite and biochar. While this method is a valid indicator test for determining a soluble Si source, other plant species and methods should be perused to potentially provide more quantitative analyses for plant-available Si content of all materials.

  11. The 6.5-day wave and its seasonal variability in the middle and upper atmosphere

    NASA Astrophysics Data System (ADS)

    Liu, H.-L.; Talaat, E. R.; Roble, R. G.; Lieberman, R. S.; Riggin, D. M.; Yee, J.-H.

    2004-11-01

    The zonal wave number 1 planetary wave of period near 6.5 days is a robust feature in the mesosphere and lower thermosphere (MLT) region with prominent seasonal variability as revealed by ground based and satellite observations. This wave and its seasonal variability are well reproduced in a recent one model year run of the National Center for Atmospheric Research thermosphere-ionosphere-mesosphere-electrodynamics general circulation model (TIME-GCM) with its lower boundary specified according to the National Centers for Environmental Prediction analysis (year 1993). Wavelet analysis of the model output shows that in the MLT region the wave maximizes before and after the equinoxes and minimizes at solstices. The wave amplitudes at the equinoxes are smaller than the peaks before and after but are still larger than the wave amplitudes at solstices. However, at the lower boundary near 30 km the wave peaks are predominantly between fall and the following spring. By examining the episodes of maximum and minimum wave amplitude and by conducting additional control experiments using the TIME-GCM, the structure of this planetary wave and the factors determining the wave characteristics and seasonal variability are studied in detail. It is found that the wave source, mean wind structure, instability, and the critical layers of the wave can all affect the wave response in the MLT region and can have a strong seasonal dependence. Before and after equinox, the wave follows the waveguide and propagates from the stratosphere to the summer mesosphere/mesopause, where it may amplify due to baroclinic/barotropic instability. Such instability is usually absent from the equinoctial atmosphere, so that there is no wave amplification at equinox. At solstice the wave decays significantly when propagating away from its winter source due to the strong eastward winter stratospheric jet. In the summer side the westward jet is also strong, and the meridional and vertical extension of the

  12. 5-day storage of platelet concentrates in CLX containers: effect of type of agitation.

    PubMed

    Snyder, E L; Bookbinder, M; Kakaiya, R; Ferri, P; Kiraly, T

    1983-01-01

    To determine the degree of platelet damage produced by different modes of agitation during storage of concentrates for 5 days in CLX blood bags, we studied pH, platelet counts, release of LDH and beta thromboglobulin, morphology and osmotic recovery. Platelets were maintained at 20-24 degrees C on elliptical, 6-rpm circular, 2-rpm circular and flat bed agitators. At 72-120 h platelet concentrates stored on the flat bed shaker had significantly lower pH values than units stored on the elliptical or on either of the circular rotators (p less than 0.05). The percent LDH discharged was highest for the units stored on the elliptical rotator (p less than 0.05). Remaining tests of platelet function were not significantly different for concentrates stored on any of the four agitators. Flat bed shakers were unable to resuspend the platelet 'button' which formed after the final preparative centrifugation. Based on our in vitro studies, we conclude that due to problems with low pH values, flat bed shakers may not be optimal for storing platelet concentrates in CLX blood bags and that some other form of agitation should be used.

  13. Interhemispheric structure and variability of the 5-day planetary wave from meteor radar wind measurements

    NASA Astrophysics Data System (ADS)

    Iimura, H.; Fritts, D. C.; Janches, D.; Singer, W.; Mitchell, N. J.

    2015-11-01

    A study of the quasi-5-day wave (5DW) was performed using meteor radars at conjugate latitudes in the Northern and Southern hemispheres. These radars are located at Esrange, Sweden (68° N) and Juliusruh, Germany (55° N) in the Northern Hemisphere, and at Tierra del Fuego, Argentina (54° S) and Rothera Station, Antarctica (68° S) in the Southern Hemisphere. The analysis was performed using data collected during simultaneous measurements by the four radars from June 2010 to December 2012 at altitudes from 84 to 96 km. The 5DW was found to exhibit significant short-term, seasonal, and interannual variability at all sites. Typical events had planetary wave periods that ranged between 4 and 7 days, durations of only a few cycles, and infrequent strongly peaked variances and covariances. Winds exhibited rotary structures that varied strongly among sites and between events, and maximum amplitudes up to ~ 20 m s-1. Mean horizontal velocity covariances tended to be largely negative at all sites throughout the interval studied.

  14. In vivo flow cytometric Pig-a and micronucleus assays: highly sensitive discrimination of the carcinogen/noncarcinogen pair benzo(a)pyrene and pyrene using acute and repeated-dose designs.

    PubMed

    Torous, Dorothea K; Phonethepswath, Souk; Avlasevich, Svetlana L; Mereness, Jared; Bryce, Steven M; Bemis, Jeffrey C; Weller, Pamela; Bell, Sara; Gleason, Carol; Custer, Laura L; MacGregor, James T; Dertinger, Stephen D

    2012-07-01

    Combining multiple genetic toxicology endpoints into a single in vivo study, and/or integrating one or more genotoxicity assays into general toxicology studies, is attractive because it reduces animal use and enables comprehensive comparative analysis using toxicity, metabolism, and pharmacokinetic information from the same animal. This laboratory has developed flow cytometric scoring techniques for monitoring two blood-based genotoxicity endpoints-micronucleated reticulocyte frequency and gene mutation at the Pig-a locus-thereby making combination and integration studies practical. The ability to effectively monitor these endpoints in short-term and repeated dosing schedules was investigated with the carcinogen/noncarcinogen pair benzo(a)pyrene (BP) and pyrene (Pyr). Male Sprague-Dawley rats were treated via oral gavage for 3 or 28 consecutive days with several dose levels of Pyr, including maximum tolerated doses. BP exposure was administered by the same route but at one dose level, 250 or 125 mg/kg/day for 3-day and 28-day studies, respectively. Serial blood samples were collected up to Day 45, and were analyzed for Pig-a mutation with a dual labeling method (SYTO 13 in combination with anti-CD59-PE) that facilitated mutant cell frequency measurements in both total erythrocytes and the reticulocyte subpopulation. A mutant cell enrichment step based on immunomagnetic column separation was used to increase the statistical power of the assay. BP induced robust mutant reticulocyte responses by Day 15, and elevated frequencies persisted until study termination. Mutant erythrocyte responses lagged mutant reticulocyte responses, with peak incidences observed on Day 30 of the 3-day study (43-fold increase) and on Day 42 of the 28-day study (171-fold increase). No mutagenic effects were apparent for Pyr. Blood samples collected on Day 4, and Day 29 for the 28-day study, were evaluated for micronucleated reticulocyte frequency. Significant increases in micronucleus

  15. Efficacy and tolerability of 5-day azacytidine dose-intensified regimen in higher-risk MDS.

    PubMed

    Pierdomenico, Francesca; Esteves, Susana; Almeida, Antonio

    2013-09-01

    Higher-risk myelodysplastic syndromes (MDS) are aggressive disorders with rapid progression to AML and short survival. Azacitidine has shown unprecedented survival advantage in these patients but its treatment schedule involves daily hospital administrations for 7 days every 4 weeks. Due to patient and staffing constraints, we have treated 50 patients with a 5-day dose-intensified (500 mg/m(2) total monthly dose divided in 5 days) azacitidine schedule in our center. The regimen was well tolerated, with Grade 3/4 adverse events seen in 24 % patients and only two discontinuations due to toxicity. The response rate was similar to that reported with the 7-day schedule: 16 % complete remissions, 32 % partial remissions, and 62 % transfusion independence. The median survival was 19.2 months from diagnosis. In addition, this regimen reduced hospital visits by 28 % and drug use by 30 %. Our results demonstrate the safety and efficacy of a dose-intensified 5-day regimen.

  16. Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

    PubMed

    Maschmeyer, Ilka; Hasenberg, Tobias; Jaenicke, Annika; Lindner, Marcus; Lorenz, Alexandra Katharina; Zech, Julie; Garbe, Leif-Alexander; Sonntag, Frank; Hayden, Patrick; Ayehunie, Seyoum; Lauster, Roland; Marx, Uwe; Materne, Eva-Maria

    2015-09-01

    Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at (1)/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance - troglitazone - to the chip-based co-cultures.

  17. Response of mice to continuous 5-day passive hyperthermia resembles human heat acclimation.

    PubMed

    Sareh, Houtan; Tulapurkar, Mohan E; Shah, Nirav G; Singh, Ishwar S; Hasday, Jeffrey D

    2011-05-01

    Chronic repeated exposure to hyperthermia in humans results in heat acclimation (HA), an adaptive process that is attained in humans by repeated exposure to hyperthermia and is characterized by improved heat elimination and increased exercise capacity, and acquired thermal tolerance (ATT), a cellular response characterized by increased baseline heat shock protein (HSP) expression and blunting of the acute increase in HSP expression stimulated by re-exposure to thermal stress. Epidemiologic studies in military personnel operating in hot environments and elite athletes suggest that repeated exposure to hyperthermia may also exert long-term health effects. Animal models demonstrate that coincident exposure to mild hyperthermia or prior exposure to severe hyperthermia can profoundly affect the course of experimental infection and injury, but these models do not represent HA. In this study, we demonstrate that CD-1 mice continuously exposed to mild hyperthermia (ambient temperature ~37°C causing ~2°C increase in core temperature) for 5 days and then exposed to a thermal stress (42°C ambient temperature for 40 min) exhibited some of the salient features of human HA, including (1) slower warming during thermal stress and more rapid cooling during recovery and (2) increased activity during thermal stress, as well as some of the features of ATT, including (1) increased baseline expression of HSP72 and HSP90 in lung, heart, spleen, liver, and brain; and (2) blunted incremental increase in HSP72 expression following acute thermal stress. This study suggests that continuous 5-day exposure of CD-1 mice to mild hyperthermia induces a state that resembles the physiologic and cellular responses of human HA. This model may be useful for analyzing the molecular mechanisms of HA and its consequences on host responsiveness to subsequent stresses.

  18. Outcomes of a 5-day physiotherapy programme for functional (psychogenic) motor disorders.

    PubMed

    Nielsen, G; Ricciardi, L; Demartini, B; Hunter, R; Joyce, E; Edwards, M J

    2015-03-01

    Patients with functional motor disorder (FMD) are commonly seen by physiotherapists and there is growing evidence to support a physical rehabilitation approach. There are, however, few descriptions in the literature of the content of successful physiotherapy treatment. This prospective cohort study reports the practicalities and outcomes of a pilot 5-day physiotherapy programme. Patients were referred from a specialist movement disorders clinic. The treatment consisted of education and movement retraining, with a long-term self-management focus. Education and movement retraining was based on a pathophysiological model for FMD that stresses the importance of self-focussed attention and illness belief. Patients were assessed at baseline, end of treatment and 3-month follow-up. 47 patients completed the programme, mean symptom duration was 5.5 years, 64 % were unemployed due to ill health. At the end of treatment, 65 % rated their symptoms as "very much improved" or "much improved", this reduced to 55 % at 3 months. At follow-up, there was a significant improvement in physical domains of the SF-36, Berg Balance Scale and 10 Metre Timed Walk. Measures of mental health did not change. This prospective cohort study adds to the growing evidence that supports the use of specialist physiotherapy treatment for FMD. Improvements here were made despite the cohort having characteristics associated with poor prognosis. We argue that specific treatment techniques are important and have the potential to improve physical function, quality of life and may prove to be a cost-effective treatment for selected patients with FMD.

  19. Platelet function testing during 5-day storage of single and random donor plateletpheresis.

    PubMed

    Akay, O Meltem; Gündüz, Eren; Başyiğit, Hatice; Gulbas, Zafer

    2007-06-01

    Platelet concentrates are routinely manufactured from whole blood by differential centrifugation (random donor platelets-RDP) or by plateletpheresis (single donor platelets-SDP). These platelet concentrates have a storage period of 5 days and many different approaches exist to measure the condition of platelets during their storage. In this study, platelet aggregation testing using adenosine diphosphate (ADP) and collagen and flow cytometric platelet activation analysis using CD41 FITC and CD62 PE before and after ADP was performed on days 1, 3 and 5 of storage of platelet preparations. Thirty three RDPs, stored in Baxter and Kansuk blood bags and 18 SDPs stored in Fresenius blood bags were evaluated. In RDPs and in SDPs; ADP and collagen induced PA responses were decreased significantly on the 3rd and 5th days compared to 1st day. CD62 positive platelet percentage after ADP were decreased significantly on the 3rd and 5th days compared to the 1st day in Kansuk bags. Flow cytometric analysis revealed minor changes in CD41 expression after ADP on the 3rd day compared to 1st day and on the 5th day compared to 3rd day. Differences in CD62 positive platelet percentage were not significant between the RDPs and SDPs. Our results suggest that: (1) ADP and collagen induced PA responses decrease both in RDPs and SDPs during storage. (2) Flow cytometric analysis does not show major significant changes in platelet activation after ADP during storage. (3) Continous shaking on the agitator does not cause a significant change in CD62 positive platelet percentage during storage. (4) Platelet aggregation responses in RDPs stored in Baxter and Kansuk blood bags do not differ during storage.

  20. Prediction of the Carcinogenic Potential of Human Pharmaceuticals Using Repeated Dose Toxicity Data and Their Pharmacological Properties

    PubMed Central

    van der Laan, Jan Willem; Buitenhuis, Wenny H. W.; Wagenaar, Laura; Soffers, Ans E. M. F.; van Someren, Eugene P.; Krul, Cyrille A. M.; Woutersen, Ruud A.

    2016-01-01

    In an exercise designed to reduce animal use, we analyzed the results of rat subchronic toxicity studies from 289 pharmaceutical compounds with the aim to predict the tumor outcome of carcinogenicity studies in this species. The results were obtained from the assessment reports available at the Medicines Evaluation Board of the Netherlands for 289 pharmaceutical compounds that had been shown to be non-genotoxic. One hundred forty-three of the 239 compounds not inducing putative preneoplastic lesions in the subchronic study did not induce tumors in the carcinogenicity study [true negatives (TNs)], whereas 96 compounds were categorized as false negatives (FNs) because tumors were observed in the carcinogenicity study. Of the remaining 50 compounds, 31 showed preneoplastic lesions in the subchronic study and tumors in the carcinogenicity study [true positives (TPs)], and 19 only showed preneoplastic lesions in subchronic studies but no tumors in the carcinogenicity study [false positives (FPs)]. In addition, we then re-assessed the prediction of the tumor outcome by integrating the pharmacological properties of these compounds. These pharmacological properties were evaluated with respect to the presence or absence of a direct or indirect proliferative action. We found support for the absence of cellular proliferation for 204 compounds (TN). For 67 compounds, the presence of cellular hyperplasia as evidence for proliferative action could be found (TP). Therefore, this approach resulted in an ability to predict non-carcinogens at a success rate of 92% and the ability to detect carcinogens at 98%. The combined evaluation of pharmacological and histopathological endpoints eventually led to only 18 unknown outcomes (17 categorized as FN and 1 as FP), thereby enhancing both the negative and positive predictivity of an evaluation based upon histopathological evaluation only. The data show the added value of a consideration of the pharmacological properties of compounds in

  1. Antithrombotic effect of repeated doses of the ethanolic extract of local olive (Olea europaea L.) leaves in rabbits.

    PubMed

    Dub, Abdallah M; Dugani, Aisha M

    2013-05-22

    The incidence of thromboembolic diseases is increasing, and they are a major cause of mortality and morbidity worldwide. Mediterranean diet is known for its high content of olive products, especially olive oil, which has known cardiovascular health benefits, including those on blood pressure, cholesterol level, and thrombogenesis. All previous animal and clinical studies investigating the beneficial antithrombotic effects of olives have focused on olive oil and a few on olive leaves (OLEs). In this study, the ethanolic extract of OLE was evaluated for its antithrombotic activity in the rabbit model of thrombosis induced by ligature of the vena cava and intravenous administration of tissue thromboplastin. Pre-treatment with 100 or 200 mg/kg per day of the ethanolic extract for 8 weeks significantly prolonged the prothrombin time (PT) in comparison to the control group (12.10 ± 0.35 sec and 14.38 ± 0.29 sec vs. 10.8 ± 0.32 sec, p < 0.05 and 0.001, respectively). In comparison to the control group, the same doses had no statistically significant effect on thrombus weight (16.85 ± 0.67 mg, 16.32 ± 0.35 mg, and 17.81 ± 0.75 mg; p = 0.18 and 0.06) or on activated partial thromboplastin time (APTT) (19.17 ± 0.33 sec, 19.12 ± 0.73 sec, and 18.97 ± 0.41 sec; p = 0.36 and 0.43, respectively). One important finding in this study concerns thrombus morphology. In the extract treatment groups, the thrombus was filament-like and did not adhere to blood vessel walls, whereas in the control group the thrombus was thick and almost completely occluded the vein. Therefore, these results suggest that OLE ethanolic extract can modify the extrinsic coagulation pathway as evidenced by the prolongation of PT and changes in thrombus morphology, enough to justify further research to evaluate its possible antithrombotic effects.

  2. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals

    PubMed Central

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed. PMID:28257483

  3. Adhesion of leukocytes to dermal endothelial cells is induced after single-dose, but reduced after repeated doses of UVA.

    PubMed

    Heckmann, M; Pirthauer, M; Plewig, G

    1997-12-01

    Approximately 20-50% of ultraviolet A (UVA) irradiation delivered to the skin surface may reach the human dermal microvascular endothelial cells (HDMEC) that play a pivotal role in cellular inflammatory tissue; however, the pathophysiologic role of HDMEC in UVA-induced skin changes is largely unknown. Based on previous in vivo and in vitro studies revealing UVA-induced expression of endothelial adhesion molecules, we studied isolated HDMEC under various conditions in order to further delineate the impact of UVA on these cells. The expression of cell adhesion molecules was determined by flow cytometry and the resulting changes of stable adhesion of leukocytes to endothelial cells were quantitated for granulocytes, lymphocytes, and monocytes using a newly developed multicellular adhesion assay. Additionally, antibody blocking experiments were performed to delineate the role of individual cell adhesion molecules in UVA-induced leukocyte adherence. High-dose polychromatic UVA (25 J per cm2, maximal emission at 375 nm) induced intercellular adhesion molecule-1 and E-selectin with different kinetics but correlating the adhesion of leukocyte subsets. This effect subsided, however, in the course of 3-6 daily applied UVA doses. Moreover, pro-inflammatory cytokine challenge by tumor necrosis factor-alpha and interleukin-1-alpha resulted in significantly weaker induction of intercellular adhesion molecule-1 and E-selectin in repeatedly UVA-exposed HDMEC. Differential quantitation of peripheral blood derived granulocytes, lymphocytes, and monocytes revealed reduced adhesion particularly of lymphocytes followed by monocytes and granulocytes compared with leukocyte adhesion to nonirradiated but cytokine-stimulated HDMEC. It is concluded that UVA substantially influences endothelial cell adhesion molecules expression and thus directly interferes with leukocyte adhesion to endothelial cells. Divergent UVA-induced effects in this respect can be attributed to the mode of UV exposure

  4. Short-term repeated-dose toxicity profile of archaeosomes administered to mice via intravenous and oral routes.

    PubMed

    Omri, Abdelwahab; Agnew, Brian J; Patel, Girishchandra B

    2003-01-01

    observed. Based on this limited mouse study, archaeosomes were generally well tolerated after intravenous or oral delivery at the dosages so indicated in this study.

  5. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals.

    PubMed

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

  6. Alterations in erythrocyte survival parameters in rats after 19.5 days aboard Cosmos 782

    NASA Technical Reports Server (NTRS)

    Leon, H. A.; Serova, L. V.; Cummins, J.; Landaw, S. A.

    1978-01-01

    Rats were subjected to 19.5 days of weightless space flight aboard the Soviet biosatellite, Cosmos 782. Based on the output of CO-14, survival parameters of a cohort of erythrocytes labeled 15.5 days preflight were evaluated upon return from orbit. These were compared to vivarium control rats injected at the same time. Statistical evaluation indicates that all survival factors were altered by the space flight. The mean potential lifespan, which was 63.0 days in the control rats, was decreased to 59.0 days in the flight rats, and random hemolysis was increased three-fold in the flight rats. The measured size of the cohort was decreased, lending further support to the idea that hemolysis was accelerated during some portion of the flight. A number of factors that might be contributory to these changes are discussed, including forces associated with launch and reentry, atmospheric and environmental parameters, dietary factors, radiation, and weightlessness.

  7. Biochemical changes in rat liver after 18.5 days of spaceflight (41566)

    NASA Technical Reports Server (NTRS)

    Abraham, S.; Lin, C.Y.; Volkmann, C. M.; Klein, H. P.

    1983-01-01

    The effect of weightlessness on liver metabolism was investigated using tissue from rats flown in earth orbit for 18.5 days on the Soviet Cosmos 936 biosatellite and the changes in the activities of 28 carbohydrate and lipid enzymes were determined. The activities of two enzymes, palmitoyl-CoA desaturase and lactate dehydrogenase, increased, while the activities of five, glycogen phosphorylase, 6-phosphogluconate dehydrogenase, both acyltransferases which act on alpha-glycerolphosphate and diglycerides, and and aconitate hydratase decreased. The other enzyme activities were found to be unchanged. In addition, increased levels of liver glycogen and palmitoleate were detected which probably resulted from the lowered glycogen phosphorylase and increased palmitoyl-CoA desaturase activities, respectively, in those animals that experienced weightlessness. All of the changes observed in the rats after 18.5 days of spaceflight disappear by 25 days after the flight.

  8. Comparison of prorenoate potassium and spironolactone after repeated doses and steady state plasma levels of active metabolites.

    PubMed Central

    McInnes, G T; Shelton, J R; Harrison, I R; Perkins, R M; Palmer, R F

    1982-01-01

    1 After repeated single daily doses, the aldosterone antagonists prorenoate potassium and spironolactone were compared with regard to renal antimineralocorticoid activity, plasma potassium concentration and steady state plasma levels of their active metabolites, prorenone and canrenone respectively, in a balanced crossover study of twelve healthy subjects. 2 Following challenge with the mineralocorticoid, fludrocortisone, best estimates of the potency of prorenoate potassium relative to spironolactone were 3.6 (95% confidence limits 1.6-10.4) for urinary sodium excretion and 3.4 (95% confidence limits 2.0-6.5) for urinary log10 10Na/K. Estimates with respect to urinary potassium excretion and plasma potassium concentration were imprecise, confirming the limitations of the fludrocortisone model in the evaluation of aldosterone antagonists at steady state. 3 Both compounds exhibited directly proportional relationships between daily dose and steady state plasma levels of active metabolites. The approximate mean terminal elimination half-life of prorenone at steady state was 32.6 h (range 18-80 h). PMID:7059416

  9. Sex differences in Δ(9)-tetrahydrocannabinol metabolism and in vivo pharmacology following acute and repeated dosing in adolescent rats.

    PubMed

    Wiley, Jenny L; Burston, James J

    2014-07-25

    Mechanisms that may underlie age and sex differences in the pharmacological effects of cannabinoids are relatively unexplored. The purpose of the present study was to determine whether sex differences in metabolism of Δ(9)-tetrahydrocannabinol (THC), similar to those observed previously in adult rats, also occurred in adolescent rats and might contribute to age and sex differences in its in vivo pharmacology. Male and female adolescent rats were exposed to THC acutely or repeatedly for 10 days. Subsequently, some of the rats were sacrificed and blood and brain levels of THC and one of its metabolites, 11-hydroxy-Δ(9)-THC (11-OH-THC), were measured. Other rats were evaluated in a battery of in vivo tests that are sensitive to cannabinoids. Concentrations of 11-OH-THC in the brains of female adult and adolescent rats exceeded those observed in male conspecifics, particularly after repeated THC administration. In contrast, brain levels of THC did not differ between the sexes. In vivo, acute THC produced dose-related hypothermia, catalepsy and suppression of locomotion in adolescent rats of both sexes, with tolerance developing after repeated administration. With a minor exception, sex differences in THC's effects in the in vivo assays were not apparent. Together with previous findings, the present results suggest that sex differences in pharmacokinetics cannot fully explain the patterns of sex differences (and lack of sex differences) in cannabinoid effects across behaviors. Hormonal and/or pharmacodynamic factors are also likely to play a role.

  10. INO-4995 Therapeutic Efficacy Is Enhanced with Repeat Dosing in Cystic Fibrosis Knockout Mice and Human Epithelia

    PubMed Central

    Traynor-Kaplan, Alexis E.; Moody, Mark; Nur, Magda; Gabriel, Sherif; Majerus, Philip W.; Drumm, Mitchell L.; Langton-Webster, Beatrice

    2010-01-01

    Progressive lung damage in cystic fibrosis (CF) has been linked to inadequate airway mucosal hydration. We previously demonstrated that an inositol tetrakisphosphate analog, 1-O-octyl-2-O-butyryl-myo-inositol 3,4,5,6-tetrakisphosphate octakis(propionoxymethyl)ester (INO-4995), regulates airway secretory and absorptive processes, affecting mucosal hydration by prolonged (24 h) inhibition of Na+ and fluid absorption in CF human nasal epithelia (CFHNE). The objectives of this study were to further assess clinical potential of INO-4995 in CF through ascertaining in vivo activity in mice with CF, determining the effects of repeated administration on potency and determining cytoplasmic half-life. Uptake and metabolism of [3H]INO-4995 was monitored with HPLC to calculate intracellular half-life. INO-4995 was administered in vitro repeatedly over 4 to 8 days to CFHNE. Fluid absorption was assessed by blue dextran exclusion, and basal short-circuit current was measured in Ussing chambers. INO-4995 (1–100 μg/kg) was dosed intranasally either as a single dose or once per day over 4 days to gut-corrected CF mice. [3H]INO-4995 was rapidly taken up by epithelial cultures and converted to the active drug, which had a half-life of 40 hours. Repeated daily application of INO-4995 to CFHNE lowered the effective concentration for inhibition of fluid absorption and amiloride-sensitive short-circuit current in cultured CFHNE, and reduced nasal potential difference to nearly control levels in gut-corrected CF mice. Ca2+-activated Cl− channel activity was also boosted in cultures. Mouse nasal levels fell from abnormal levels to within 2 μA of normal with repeated exposure to 0.8 μg/kg over 4 days. These data support further development of INO-4995 for the treatment of CF. PMID:19346319

  11. Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction.

    PubMed

    Guo, Yiru; Wysoczynski, Marcin; Nong, Yibing; Tomlin, Alex; Zhu, Xiaoping; Gumpert, Anna M; Nasr, Marjan; Muthusamy, Senthikumar; Li, Hong; Book, Michael; Khan, Abdur; Hong, Kyung U; Li, Qianhong; Bolli, Roberto

    2017-03-01

    We have recently demonstrated that repeated administrations of c-kit(POS) cardiac progenitor cells (CPCs) have cumulative beneficial effects in rats with old myocardial infarction (MI), resulting in markedly greater improvement in left ventricular (LV) function compared with a single administration. To determine whether this paradigm applies to other species and cell types, mice with a 3-week-old MI received one or three doses of cardiac mesenchymal cells (CMCs), a novel cell type that we have recently described. CMCs or vehicle were infused percutaneously into the LV cavity, 14 days apart. Compared with vehicle-treated mice, the single-dose group exhibited improved LV ejection fraction (EF) after the 1st infusion (consisting of CMCs) but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group, LV EF improved after each CMC infusion, so that at the end of the study, LV EF averaged 35.5 ± 0.7% vs. 32.7 ± 0.6% in the single-dose group (P < 0.05). The multiple-dose group also exhibited less collagen in the non-infarcted region vs. the single-dose group. Engraftment and differentiation of CMCs were negligible in both groups, indicating paracrine effects. These results demonstrate that, in mice with ischemic cardiomyopathy, the beneficial effects of three doses of CMCs are significantly greater than those of one dose, supporting the concept that multiple treatments are necessary to properly evaluate the full therapeutic potential of cell therapy. Thus, the repeated-treatment paradigm is not limited to c-kit (POS) CPCs or to rats, but applies to other cell types and species. The generalizability of this concept dramatically augments its significance.

  12. Evaluation of sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride. Results of a prospective, randomized, double-blind, placebo-controlled trial.

    PubMed

    Dulin, J; Kovács, L; Ramm, S; Horvath, F; Ebeling, L; Kohnen, R

    1998-07-01

    Sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride (Mydocalm), a centrally active muscle-relaxing agent, were evaluated in a placebo-controlled double-blind clinical trial. A total of 72 healthy young adults balanced by sex were randomized to receive 50 mg or 150 mg tolperisone hydrochloride or placebo t.i.d. for a period of 8 days. Control examinations were performed in the mornings of days 1 and 8 before intake of the morning dose and at 1.5, 4 and 6 hours postdose. The psychomotoric test battery used in this trial revealed no sedative effects of tolperisone hydrochloride in the given doses at any control examination. Subjective mood ratings quantified by the Welzel Colored Scales were not impaired either. The lack of differences in sedative potentials of tolperisone hydrochloride and placebo was confirmed by tests on differences and by tests on equivalence using 95% CI. The present study substantiates clinical experience and previous clinical trials demonstrating that tolperisone hydrochloride, though being a centrally active muscle relaxant, does not cause any sedation and does not impair reaction times.

  13. Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

    PubMed

    Wilding, Laura A; Bassis, Christine M; Walacavage, Kim; Hashway, Sara; Leroueil, Pascale R; Morishita, Masako; Maynard, Andrew D; Philbert, Martin A; Bergin, Ingrid L

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome.

  14. Playback Station #2 for Cal Net and 5-day-recorder tapes

    USGS Publications Warehouse

    Eaton, Jerry P.

    1978-01-01

    A second system (Playback Station #2) has been set up to play back Cal Net 1" tapes and 5-day-recorder 1/2" tapes. As with the first playback system (Playback Station #1) the tapes are played back on a Bell and Howell VR3700B tape deck and the records are written out on a 16-channel direct-writing Siemens "0scillomink." Separate reproduce heads, tape guides, and tape tension sensor rollers are required for playing back 111 tapes and 1/2" tapes, but changing these tape deck components is a simple task that requires only a few minutes. The discriminators, patch panels, selector switches, filters, time code translators, and signal conditioning circuits for the time code translators and for the tape-speed-compensation signal are all mounted in an equipment rack that stands beside the playback tape deck. Changing playback speeds (15/16 ips or 3 3/4 ips) or changing from Cal Net tapes to 5-day-recorder tapes requires only flipping a few switches and/or changing a few patch cables on the patch panel (in addition to changing the reproduce heads, etc., to change from 1" tape to 1/2" tape). For the Cal Net tapes, the system provides for playback of 9 data channels (680 Hz thru 3060 Hz plus 400 Hz) and 3 time signals (IRIG-E, IRIG-C, and WWVB) at both 15/16 ips (x1 speed) and 3 3/4 ips (x4 speed). Available modes of compensation (using either a 4688 Hz reference or a 3125 Hz reference) are subtractive, capstan, capstan plus subtractive, or no compensation.

  15. Preosteoblast production 55 hours after a 12.5-day spaceflight on Cosmos 1887.

    PubMed

    Garetto, L P; Gonsalves, M R; Morey, E R; Durnova, G; Roberts, W E

    1990-01-01

    The influence of 12.5 days of spaceflight and a 55 h stressful recovery period (at 1 g) on fibroblastlike osteoblast precursor cells was assessed in the periodontal ligament (PDL) of rats that were 91 days old at launch. Nuclear morphometry was used as a marker for precursor cell differentiation in 3 microns sections cut in the midsagittal plane from the maxillary first molar. According to nuclear volume, cells were classified as preosteoblasts (C + D cells, greater than or equal to 120 microns 3) and less differentiated progenitor cells (A + A' cells, 40-79 microns 3). Compared with synchronous controls (simulated flight conditions), the 55 h postflight recovery period at 1 g resulted in a 40% decrease in the A + A' cell population, a 42% increase in the C + D cells, and a 39% increase in the number of PDL fibroblastlike cells near the bone surface. These results are consistent with a postflight osteogenic response in PDL. This recovery response occurred despite physiological stress in the flight animals that resulted in a highly significant (P less than or equal to 0.001) increase in adrenal weight. The data suggest that after spaceflight there is a strong and rapid recovery mechanism for osteoblast differentiation that is not suppressed by physiological stress.

  16. Preosteoblast production 55 hours after a 12.5-day spaceflight on Cosmos 1887

    NASA Technical Reports Server (NTRS)

    Garetto, L. P.; Gonsalves, M. R.; Morey, E. R.; Durnova, G.; Roberts, W. E.; Morey-Holton, E. (Principal Investigator)

    1990-01-01

    The influence of 12.5 days of spaceflight and a 55 h stressful recovery period (at 1 g) on fibroblastlike osteoblast precursor cells was assessed in the periodontal ligament (PDL) of rats that were 91 days old at launch. Nuclear morphometry was used as a marker for precursor cell differentiation in 3 microns sections cut in the midsagittal plane from the maxillary first molar. According to nuclear volume, cells were classified as preosteoblasts (C + D cells, greater than or equal to 120 microns 3) and less differentiated progenitor cells (A + A' cells, 40-79 microns 3). Compared with synchronous controls (simulated flight conditions), the 55 h postflight recovery period at 1 g resulted in a 40% decrease in the A + A' cell population, a 42% increase in the C + D cells, and a 39% increase in the number of PDL fibroblastlike cells near the bone surface. These results are consistent with a postflight osteogenic response in PDL. This recovery response occurred despite physiological stress in the flight animals that resulted in a highly significant (P less than or equal to 0.001) increase in adrenal weight. The data suggest that after spaceflight there is a strong and rapid recovery mechanism for osteoblast differentiation that is not suppressed by physiological stress.

  17. Shoot growth in aseptically cultivated daylily and haplopappus plantlets after a 5-day spaceflight

    NASA Technical Reports Server (NTRS)

    Levine, H. G.; Krikorian, A. D.

    1992-01-01

    Plantlets of daylily (Hemerocallis cv. Autumn Blaze) regenerated from cell suspensions, and 4 clonal populations of Haplopappus gracilis were aseptically cultivated aboard the Shuttle "Discovery" during a 5-day mission within NASA's Plant Growth Unit (PGU) apparatus. Daylily was selected as a representative herbaceous perennial monocotyledon and the haplopappus clones represented an annual dicotyledon. The latter included 4 strains with different physiological and morphological characteristics: two aseptic seedling clones (each generated from a single seedling) and two tissue culture-derived lines. Mean daily growth rates for the primary shoots of all plantlets averaged 4.13 mm day-1 (SD = 2.20) for the flight experiment and 4.68 mm day-1 (SD = 2.59) for the ground control. Comparable growth rates calculated by summing both the primary and secondary shoots for all plantlets were 5.94 mm day-1 (SD = 2.89) for the flight experiment and 6.38 mm day-1 (SD = 3.71) for the control. Statistically significant differences existed between: (1) flight vs control primary shoot growth (the controls growing more than plantlets subjected to spaceflight conditions), (2) the different populations (the daylily gaining more shoot material than any of the haplopappus populations and the haplopappus seedling clones outperforming the tissue culture-derived haplopappus lines), and (3) the individual Plant Growth Chambers contained within the PGU. The data suggest that some spaceflight-associated factor(s) increased the tendency for primary shoot apices to degrade or senesce, resulting in the release of apical dominance and permitting the emergence of axillary branches, which subsequently partially compensated for the reduced primary axis growth. In addition to spaceflight-associated factors, the physiologically diverse nature of the experimental material as well as environmental heterogeneities within the culture apparatus contributed to the variation in growth results. The findings

  18. Comparison of the effects of adenine-ribose with adenosine for maintenance of ATP concentrations in 5-day hypothermically perfused dog kidneys.

    PubMed

    McAnulty, J F; Southard, J H; Belzer, F O

    1988-10-01

    The quality of preservation of kidneys is dependent upon a number of factors, one of which may be the concentration of adenine nucleotides in the tissue during long-term perfusion preservation. In this study we have investigated how adenine (5 mM) and ribose (5 mM) in combination affect the concentration of adenine nucleotides in dog kidney cortical tissue after 5 days of continuous hypothermic perfusion preservation. These results were compared to kidneys perfused with adenosine and without any added purine precursors of adenine nucleotide synthesis. Additionally, we investigated how these conditions affected renal tissue slice function after 5 days of preservation and how adenine plus ribose affected renal function after autotransplantation in the dog. Adenosine is nearly completely degraded during 5 days of perfusion but there was little loss of adenine (10%). The adenosine triphosphate concentration in kidney cortical tissue was higher in adenine/ribose-perfused kidneys (1.41 +/- 0.19 mumol/g) than in adenosine-perfused kidneys (0.71 +/- 0.1 mumol/g) after 5 days of preservation. Tissue slices prepared from kidneys preserved in the presence of adenine plus ribose were metabolically more functional (slice volume control and electrolyte pump activity) than slices from adenosine-perfused kidneys. Adenine plus ribose had no detrimental effects on kidneys preserved for 3 days as tested in the autotransplant model but did not yield successful 5-day preservation. Because of some potentially detrimental factors in using adenosine as an adenine nucleotide synthesis precursor, we have now switched to the combination of adenine and ribose for perfusion preservation of kidneys both in the laboratory and in the clinic.

  19. Effects of endurance training on endocrine response to physical exercise after 5 days of bed rest in healthy male subjects.

    PubMed

    Koska, Juraj; Ksinantová, Lucia; Kvetnanský, Richard; Hamar, Dusan; Martinkovic, Miroslav; Vigas, Milan

    2004-06-01

    The study was designed to evaluate how a bout of endurance training (ET) influences the endocrine response after head-down bed rest (HDBR). Eleven healthy males completed the study, which consisted of a 6-wk ET followed by 5 days of -6 degrees head-down HDBR. Treadmill exercise at 80% of pretraining maximal aerobic capacity (VO(2max)) was performed before and after ET as well as after HDBR. ET increased VO(2max) by 13%. The response of norepinephrine was attenuated after ET and exaggerated after HDBR (P < 0.001). The differences in epinephrine responses were not statistically significant. The responses of cortisol and plasma renin activity (PRA) were unchanged after ET and were enhanced after HDBR (P < 0.001). The response of growth hormone after HDBR was reduced (P < 0.05). Only the change in cortisol response was associated with the increment of VO(2max) after ET (r = 0.68, P < 0.01). Endurance training failed to completely prevent changes in endocrine responses seen after HDBR. Improvement of physical fitness was associated with an enhancement of the cortisol response to exercise following the period of bed rest.

  20. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

    PubMed Central

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

  1. A 90-day repeated dose oral (gavage) toxicity study of perfluorohexanoic acid (PFHxA) in rats (with functional observational battery and motor activity determinations).

    PubMed

    Chengelis, Christopher P; Kirkpatrick, Jeannie B; Radovsky, Ann; Shinohara, Motoki

    2009-06-01

    Possible toxic effects of perfluorohexanoic acid (PFHxA) were evaluated when administered orally by gavage to rats at levels up to 200mg/kg/day for 90 days. Lower body weight gains were noted in the 10, 50 and 200mg/kg/day group males (not dose-responsive) throughout dosing. Other changes included lower red blood cell parameters, higher reticulocyte counts and lower globulin in the 200mg/kg/day group males and females, higher liver enzymes in males at 50 and 200mg/kg/day, lower total protein and higher albumin/globulin ratio, and lower cholesterol, calcium in males at 200mg/kg/day. Minimal centrilobular hepatocellular hypertrophy was present in 200mg/kg/day group males and correlated with higher liver weights and slightly higher peroxisome beta oxidation activity at the end of the dosing period. Based on liver histopathology and liver weight changes, the no-observed-adverse-effect level (NOAEL) for oral administration was 50mg/kg/day for males and 200mg/kg/day for females.

  2. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study.

    PubMed

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3(+), CD4(+), CD8(+), and CD19(+)) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs.

  3. Impact of a 5-Day Expedition to Machu Picchu on Persons with Multiple Sclerosis

    PubMed Central

    D'hooghe, Marie Beatrice; Feys, Peter; Deltour, Sam; Van de Putte, Isabelle; De Meue, Jan; Kos, Daphne; O Eijnde, Bert; Van Asch, Paul

    2014-01-01

    Persons with multiple sclerosis (MS) are less physically active than nondiseased persons and often report low self-efficacy levels. In the context of an awareness project to promote physical activity and participation in MS, we addressed the impact of training for and participation in a unique expedition. Medical events, relapses, and self-reported neurological worsening were followed from 6 months before and up to 4 months afterwards. Validated patient-reported outcome measures were used to assess fatigue, self-efficacy in exercising, walking abilities, and illness perception. Nine participants completed the training, expedition, and observational study. Minor events, relapses, and/or neurological worsening were reported in six participants. The three participants with mild disability and no cardiovascular risk factors or comorbidities were free of medical and neurological events. We found a significant reduction of motor fatigue at last when compared with the first assessment. The reduction tended to be more evident in participants with mild disability (Expanded Disability Status Scale (EDSS) <4 at baseline). Cognitive fatigue, self-efficacy, and self-reported walking abilities did not change significantly. Illness perceptions tended to be reduced over time in the domains of consequences, identity, and concerns. Overall, no major adverse events occurred. PMID:24967103

  4. Translocation and biokinetic behavior of nanoscaled europium oxide particles within 5 days following an acute inhalation in rats.

    PubMed

    Creutzenberg, Otto; Kock, Heiko; Schaudien, Dirk

    2016-03-01

    Nanoscaled europium oxide (Eu2O3) particles were inhaled by rats after acute exposure and the potential translocation of particles followed by chemical analysis and transmission electron microscopy (TEM) was investigated. An aqueous dispersion (phosphate buffer/bovine serum albumin) of a commercially available Eu2O3 particle fraction consisting partially of nanoscaled particles was aerosolized with pressurized air. After rapid evaporation, rats inhaled the dry aerosol for 6 h in a single exposure resulting in an alveolar calculated dose of approximately 39.5 μg Eu2O3. Using chemical analysis, 36.8 μg Eu2O3 was detected 1 h after lung inhalation. The amount declined slightly to 34.5 μg after 1 day and 35.0 μg after 5 days. The liver showed an increase of Eu2O3 from 32.3 ng 1 h up to 294 ng 5 days after inhalation. Additionally, lung-associated lymph nodes, thymus, kidneys, heart and testis exhibited an increase of europium over the period investigated. In the blood, the highest amount of europium was found 1 h after treatment whereas feces, urine and mesenteric lymph nodes revealed the highest amount 1 day after treatment. Using TEM analysis, particles could be detected only in lungs, and in the liver, no particles were detectable. In conclusion, the translocation of Eu2O3 within 5 days following inhalation could be determined very precisely by chemical analysis. A translocation of Eu2O3 particulate matter to liver was not detectable by TEM analysis; thus, the overproportional level of 0.8% of the lung load observed in the liver after 5 days suggests a filtering effect of dissolved europium with accumulation.

  5. Initiation of GnRH agonist treatment on 3-5 days postoperatively in endometriosis patients: a randomized controlled trial.

    PubMed

    Gong, Lili; Zhang, Shaofen; Han, Yi; Long, Qiqi; Zou, Shien; Cao, Yuankui

    2015-08-01

    Seventy patients with stage III or IV endometriosis were randomly assigned to 2 groups after conservative surgery. Group O (n = 35) received 3 cycles of a 28-day gonadotropin-releasing hormone agonist (GnRH-a) treatment (goserelin, 3.6 mg) starting 3-5 days postoperatively. Group M (n = 35) received the same treatment starting on days 1-5 of menstruation. Groups were further subdivided according to add-back treatment. Pre- and posttreated levels of estradiol (E2 ), follicle stimulating hormone (FSH), and luteinizing hormone (LH) and visual analog scale (VAS), Kupperman menopausal index (KMI), and bone mineral density (BMD) scores were recorded. The incidence of uterine bleeding was assessed. In both groups, serum levels of E2 , FSH, and LH and VAS scores decreased significantly after treatment. Spotting was the most frequent bleeding pattern. During cycle 1, the bleeding time in group M was much longer that than that in group O (P =.001), and the bleeding rate in group M was significantly higher than that in group O (P =.024, RR = 1.185). In patients with stage III or IV endometriosis, the efficacy of GnRH-a initiated 3-5 days postoperatively was equivalent to that of GnRH-a initiated on days 1-5 of menstruation. Female patients who initiated GnRH-a treatment 3-5 days postoperatively experienced less uterine bleeding during the first cycle of treatment.

  6. Responses of the lower thermospheric temperature to the 9 day and 13.5 day oscillations of recurrent geomagnetic activity

    NASA Astrophysics Data System (ADS)

    Jiang, Guoying; Wang, Wenbin; Xu, Jiyao; Yue, Jia; Burns, Alan G.; Lei, Jiuhou; Mlynczak, Martin G.; Rusell, James M.

    2014-06-01

    Responses of the lower thermospheric temperature to the 9 day and 13.5 day oscillations of recurrent geomagnetic activity and solar EUV radiation have been investigated using neutral temperature data observed by the TIMED/SABER (Thermosphere Ionosphere Mesosphere Energetics and Dynamics/Sounding of the Atmosphere using Broadband Emission Radiometry) instrument and numerical experiments by the NCAR-TIME-GCM (National Center for Atmospheric Research-thermosphere-ionosphere-mesosphere electrodynamics-general circulation model). The TIMED/SABER data analyzed were for the period from 2002 to 2007 during the declining phase of solar cycle 23. The observations show that the zonal mean temperature in the lower thermosphere oscillated with periods of near 9 and 13.5 days in the height range of 100-120 km. These oscillations were more strongly correlated with the recurrent geomagnetic activity than with the solar EUV variability of the same periods. The 9 day and 13.5 day oscillations of lower thermospheric temperature had greater amplitudes at high latitudes than at low latitudes; they also had larger amplitudes at higher altitudes, and the oscillations could penetrate down to ~105 km, depending on the strength of the recurrent geomagnetic activity for a particular time period. The data further show that the periodic responses of the lower thermospheric temperature to recurrent geomagnetic activity were different in the two hemispheres. In addition, numerical experiments have been carried out using the NCAR-TIME-GCM to investigate the causal relationship between the temperature oscillations and the geomagnetic activity and solar EUV variations of the same periods. Model simulations showed the same periodic oscillations as those seen in the observations when the real geomagnetic activity index, Kp, was used to drive the model. These numerical results show that recurrent geomagnetic activity is the main cause of the 9 day and 13.5 day variations in the lower thermosphere

  7. The effect of a single high dose of PGF2α administered to dairy cattle 3.5 days after ovulation on luteal function, morphology, and follicular dynamics.

    PubMed

    Cuervo-Arango, J; García-Roselló, E; García-Muñoz, A; Valldecabres-Torres, X; Martínez-Ros, P; González-Bulnes, A

    2011-12-01

    A single treatment with PGF2α is assumed to have no luteolytic effect on cows with corpora lutea < 5 days old. The objective of this study was to determine the effect of a single high dose of PGF2α administered to dairy cattle on the morphology and function of the early CL. The study followed a crossover design with a treatment cycle in which 50 mg of dinoprost were administered 3.5 days postovulation and a control untreated cycle. Ultrasound examination and blood samples were performed during the two consecutive cycles. Corpus luteum (CL) diameter, progesterone concentration, and follicular dynamics characteristics were compared between control and treated cycles. Two of nine cows (22%) developed full luteolysis. The remaining seven cows (78%) had partial luteolysis with a decrease (P < 0.05) in progesterone concentration and CL diameter for two and 12 days post-treatment, respectively. The interovulatory interval of treated cycles (19.7 ± 2.4 days) was not different (P > 0.05) from that of controls (23.8 ± 0.9 days). The transient reduction in progesterone of cows with partial luteolysis had no effect on the proportion of cows with two or three follicular waves, follicle growth rate, or preovulatory diameter (P > 0.05). Two cows developed ovarian cystic degeneration during the PGF2α-induced cycle. In conclusion, the treatment of cows with a high dose of PGF2α 3.5 days postovulation induced some degree of luteolysis in all treated cows. This resulted in partial luteolysis in 78% of treated animals and in full luteolysis in the remaining 22%.

  8. Effectiveness of short-course therapy (5 days) with grepafloxacin in the treatment of acute bacterial exacerbations of chronic bronchitis.

    PubMed

    DeAbate, C A; Bettis, R; Munk, Z M; Fleming, H; Munn, N J; Riffer, E; Bagby, B; Giguere, G; Collins, J J

    1999-01-01

    Three hundred eighty-nine patients were enrolled in a double-masked, multicenter, randomized clinical trial comparing the clinical and bacteriologic efficacies and safety of a 5-day course (n = 195) versus a 10-day course (n = 194) of grepafloxacin 400 mg once daily in the treatment of acute bacterial exacerbations of chronic bronchitis (ABECB). Patients in the 5-day treatment group received placebo on days 6 through 10. Bacteriologic assessments were based on cultures of sputum specimens obtained before and, when possible, during and after treatment. Organisms were isolated from the pretreatment sputum specimens of 332 of 388 (86%) patients, the primary pathogens being Haemophilus parainfluenzae, Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus (29%, 19%, 4%, 5%, and 5% of isolates, respectively). Among isolates tested for beta-lactamase production, results were positive in 25% of H influenzae isolates and 90% of M catarrhalis isolates. Forty-two percent of S pneumoniae isolates demonstrated reduced susceptibility (intermediate or high-level resistance) to penicillin. A satisfactory clinical outcome (cure or improvement) was achieved in 83% (128 of 155) and 81% (122 of 150) of clinically evaluable patients treated with grepafloxacin for 5 or 10 days, respectively. Pathogens were eradicated or presumed eradicated in 77% (106 of 138) and 80% (98 of 123) of bacteriologically evaluable patients treated with grepafloxacin for 5 or 10 days, respectively. The 2 treatment groups were equivalent with respect to both clinical and bacteriologic efficacy, and no statistically significant differences in the incidence of drug-related adverse events were seen between the 2 groups. Substantial symptom relief was evident with both treatment regimens by the first during-treatment measurement, which occurred between days 3 through 5. These results indicate that treatment with 400 mg grepafloxacin once daily for 5 days is as well

  9. Daily Profiles of Fibrinogen Metabolism for 5 Days Following Hemorrhage and Lactated Ringer’s Resuscitation in Pigs

    DTIC Science & Technology

    2012-01-01

    DAILY PROFILES OF FIBRINOGEN METABOLISM FOR 5 DAYS FOLLOWING HEMORRHAGE AND LACTATED RINGER’S RESUSCITATION IN PIGS Wenjun Z. Martini , Kevin K. Chung...for measurement of mean arterial pressure 605 SHOCK, Vol. 37, No. 6, pp. 605 610, 2012 Address reprint requests to Wenjun Z. Martini , PhD, The US...Ringerâs Resuscitation in Pigs 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Martini W. Z., Chung K. K., Dubick M. A

  10. Development and validation of a 5-day-ahead hay fever forecast for patients with grass-pollen-induced allergic rhinitis.

    PubMed

    de Weger, Letty A; Beerthuizen, Thijs; Hiemstra, Pieter S; Sont, Jacob K

    2014-08-01

    One-third of the Dutch population suffers from allergic rhinitis, including hay fever. In this study, a 5-day-ahead hay fever forecast was developed and validated for grass pollen allergic patients in the Netherlands. Using multiple regression analysis, a two-step pollen and hay fever symptom prediction model was developed using actual and forecasted weather parameters, grass pollen data and patient symptom diaries. Therefore, 80 patients with a grass pollen allergy rated the severity of their hay fever symptoms during the grass pollen season in 2007 and 2008. First, a grass pollen forecast model was developed using the following predictors: (1) daily means of grass pollen counts of the previous 10 years; (2) grass pollen counts of the previous 2-week period of the current year; and (3) maximum, minimum and mean temperature (R (2)=0.76). The second modeling step concerned the forecasting of hay fever symptom severity and included the following predictors: (1) forecasted grass pollen counts; (2) day number of the year; (3) moving average of the grass pollen counts of the previous 2 week-periods; and (4) maximum and mean temperatures (R (2)=0.81). Since the daily hay fever forecast is reported in three categories (low-, medium- and high symptom risk), we assessed the agreement between the observed and the 1- to 5-day-ahead predicted risk categories by kappa, which ranged from 65 % to 77 %. These results indicate that a model based on forecasted temperature and grass pollen counts performs well in predicting symptoms of hay fever up to 5 days ahead.

  11. Development and validation of a 5-day-ahead hay fever forecast for patients with grass-pollen-induced allergic rhinitis

    NASA Astrophysics Data System (ADS)

    de Weger, Letty A.; Beerthuizen, Thijs; Hiemstra, Pieter S.; Sont, Jacob K.

    2014-08-01

    One-third of the Dutch population suffers from allergic rhinitis, including hay fever. In this study, a 5-day-ahead hay fever forecast was developed and validated for grass pollen allergic patients in the Netherlands. Using multiple regression analysis, a two-step pollen and hay fever symptom prediction model was developed using actual and forecasted weather parameters, grass pollen data and patient symptom diaries. Therefore, 80 patients with a grass pollen allergy rated the severity of their hay fever symptoms during the grass pollen season in 2007 and 2008. First, a grass pollen forecast model was developed using the following predictors: (1) daily means of grass pollen counts of the previous 10 years; (2) grass pollen counts of the previous 2-week period of the current year; and (3) maximum, minimum and mean temperature ( R 2 = 0.76). The second modeling step concerned the forecasting of hay fever symptom severity and included the following predictors: (1) forecasted grass pollen counts; (2) day number of the year; (3) moving average of the grass pollen counts of the previous 2 week-periods; and (4) maximum and mean temperatures ( R 2 = 0.81). Since the daily hay fever forecast is reported in three categories (low-, medium- and high symptom risk), we assessed the agreement between the observed and the 1- to 5-day-ahead predicted risk categories by kappa, which ranged from 65 % to 77 %. These results indicate that a model based on forecasted temperature and grass pollen counts performs well in predicting symptoms of hay fever up to 5 days ahead.

  12. Evaluation of 90-day Repeated Dose Oral Toxicity, Glycometabolism, Learning and Memory Ability, and Related Enzyme of Chromium Malate Supplementation in Sprague-Dawley Rats.

    PubMed

    Feng, Weiwei; Wu, Huiyu; Li, Qian; Zhou, Zhaoxiang; Chen, Yao; Zhao, Ting; Feng, Yun; Mao, Guanghua; Li, Fang; Yang, Liuqing; Wu, Xiangyang

    2015-11-01

    Our previous study showed that chromium malate improved the regulation of blood glucose in mice with alloxan-induced diabetes. The present study was designed to evaluate the 90-day oral toxicity of chromium malate in Sprague-Dawley rats. The present study inspected the effect of chromium malate on glycometabolism, glycometabolism-related enzymes, lipid metabolism, and learning and memory ability in metabolically healthy Sprague-Dawley rats. The results showed that all rats survived and pathological, toxic, feces, and urine changes were not observed. Chromium malate did not cause measurable damage on liver, brain, and kidney. The fasting blood glucose, serum insulin, insulin resistance index, C-peptide, hepatic glycogen, glucose-6-phosphate dehydrogenase, glucokinase, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels of normal rats in chromium malate groups had no significant change when compared with control group and chromium picolinate group under physiologically relevant conditions. The serum and organ content of Cr in chromium malate groups had no significant change compared with control group. No significant changes were found in morris water maze test and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and true choline esterase (TChE) activity. The results indicated that supplementation with chromium malate did not cause measurable toxicity and has no obvious effect on glycometabolism and related enzymes, learning and memory ability, and related enzymes and lipid metabolism of female and male rats. The results of this study suggest that chromium malate is safe for human consumption.

  13. Central nervous system effects of the interaction between risperidone (single dose) and the 5-HT6 antagonist SB742457 (repeated doses) in healthy men

    PubMed Central

    Liem-Moolenaar, Marieke; Rad, Mandana; Zamuner, Stefano; Cohen, Adam F; Lemme, Francesca; Franson, Kari L; van Gerven, Joop M A; Pich, Emilio Merlo

    2011-01-01

    AIM Several lines of evidence suggest a possible role of 5-HT6receptor antagonists in cognitive dysfunction of schizophrenia. Atypical antipsychotics, such as risperidone, are currently used in these disorders. Therefore, the pharmacological interactions between the 5-HT6 antagonist SB-742457 and risperidone were investigated in the light of possible co-medication. METHODS A randomized, double-blind, two-way crossover design was used to study the interaction between multiple doses SB-742457 50 mg and a single dose risperidone 2 mg in 18 healthy subjects. RESULTS Treatment was well tolerated. The most common adverse event was somnolence in 83% during the combination vs. 50% of subjects after risperidone, 32% after placebo and 11% after SB-742457. Combination treatment produced a statistically significant increase in the maximum plasma concentration of risperidone and had no effect on SB-742457 pharmacokinetics. Risperidone decreased saccadic peak velocity, finger tapping, adaptive tracking, subjective alertness, delayed word recognition and body sway and increased electroencephalogram (EEG) theta power and prolactin. The only pharmacodynamic interaction of risperidone and SB-742457 was an increase of absolute EEG alpha (ratio = 1.25, 95% CI = 1.11, 1.40, P = 0.0004) and beta power (ratio = 1.14, 95% CI = 1.03, 1.27, P = 0.016). No significant effects of SB-742457 alone were found. CONCLUSION The pharmacokinetic interactions between SB-742457 and risperidone detected in this study were not clinically relevant. The increase in EEG alpha and beta power is incompatible with enhanced risperidone activity, but could point to mild arousing effects of the combination. Most pharmacodynamic changes of risperidone are consistent with previously reported data. The potential cognitive effects of SB-742457 remain to be established. PMID:21223356

  14. Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects.

    PubMed

    Winter, Helen; Egizi, Erica; Murray, Stephen; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J; Severynse-Stevens, Diana; Pauli, Elliott

    2015-02-01

    This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

  15. Evaluation of the Pharmacokinetic Interaction between Repeated Doses of Rifapentine or Rifampin and a Single Dose of Bedaquiline in Healthy Adult Subjects

    PubMed Central

    Winter, Helen; Egizi, Erica; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J.; Severynse-Stevens, Diana; Pauli, Elliott

    2014-01-01

    This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0–t), and AUC extrapolated to infinity (AUC0–inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0–t, and AUC0–inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0–t, and AUC0–inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier

  16. Hemoglobin induced lung vascular oxidation, inflammation, and remodeling contributes to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeat dose haptoglobin administration

    PubMed Central

    Baek, Jin Hyen; Hassell, Kathryn; Nuss, Rachelle; Eigenberger, Paul; Lisk, Christina; Loomis, Zoe; Maltzahn, Joanne; Stenmark, Kurt R; Nozik-Grayck, Eva

    2015-01-01

    Objective Haptoglobin (Hp) is an approved treatment in Japan with indications for trauma, burns and massive transfusion related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia mediated PH. Approach and results Rats were simultaneously exposed to chronic Hb-infusion (35 mg per day) and hypobaric hypoxia for five weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated non-heme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right ventricular hypertrophy, which suggest a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. Conclusions By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia; and (2) suggest a novel therapy for chronic hemolysis associated PH. PMID:25656991

  17. Hemoglobin-induced lung vascular oxidation, inflammation, and remodeling contribute to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeated-dose haptoglobin administration.

    PubMed

    Irwin, David C; Baek, Jin Hyen; Hassell, Kathryn; Nuss, Rachelle; Eigenberger, Paul; Lisk, Christina; Loomis, Zoe; Maltzahn, Joanne; Stenmark, Kurt R; Nozik-Grayck, Eva; Buehler, Paul W

    2015-05-01

    Haptoglobin (Hp) is an approved treatment in Japan for trauma, burns, and massive transfusion-related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia-mediated PH. Rats were simultaneously exposed to chronic Hb infusion (35 mg per day) and hypobaric hypoxia for 5 weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated nonheme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right-ventricular hypertrophy, which suggests a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia and (2) suggest a novel therapy for chronic hemolysis-associated PH.

  18. Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

    PubMed

    Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

    2014-05-01

    In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

  19. Interactions between cannabidiol and Δ(9)-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway.

    PubMed

    Todd, Stephanie M; Zhou, Cilla; Clarke, David J; Chohan, Tariq W; Bahceci, Dilara; Arnold, Jonathon C

    2017-02-01

    The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive.

  20. Efficacy and safety of 3 versus 5 days of meloxicam as an analgesic for feline onychectomy and sterilization

    PubMed Central

    Ingwersen, Walt; Fox, Ronald; Cunningham, Gail; Winhall, Martha

    2012-01-01

    Three- or 5-day courses of meloxicam [0.2 mg/kg body weight (BW) subcutaneously pre- or postoperatively on Day 1 followed by 0.05 mg/kg BW, PO per day thereafter] were assessed for analgesic efficacy and safety in 50 client-owned cats undergoing onychectomy and sterilization. Primary outcome parameters were analgesia score, gait/lameness score, and need for rescue analgesia assessed at times 0, 1, 4, 7, 24, 28, 35, 48, 52, 57 hours and on Day 5. Packed cell volume/total solids and serum biochemistry were assessed at time 0 and Days 3 and 5. There were no differences in efficacy and safety parameters regardless of the treatment protocol employed and no cat required rescue analgesia. The patients that received meloxicam preoperatively had statistically better gait/lameness scores than those that received meloxicam postoperatively, supporting the principle of preemptive analgesia. PMID:22942440

  1. Efficacy and safety of 3 versus 5 days of meloxicam as an analgesic for feline onychectomy and sterilization.

    PubMed

    Ingwersen, Walt; Fox, Ronald; Cunningham, Gail; Winhall, Martha

    2012-03-01

    Three- or 5-day courses of meloxicam [0.2 mg/kg body weight (BW) subcutaneously pre- or postoperatively on Day 1 followed by 0.05 mg/kg BW, PO per day thereafter] were assessed for analgesic efficacy and safety in 50 client-owned cats undergoing onychectomy and sterilization. Primary outcome parameters were analgesia score, gait/lameness score, and need for rescue analgesia assessed at times 0, 1, 4, 7, 24, 28, 35, 48, 52, 57 hours and on Day 5. Packed cell volume/total solids and serum biochemistry were assessed at time 0 and Days 3 and 5. There were no differences in efficacy and safety parameters regardless of the treatment protocol employed and no cat required rescue analgesia. The patients that received meloxicam preoperatively had statistically better gait/lameness scores than those that received meloxicam postoperatively, supporting the principle of preemptive analgesia.

  2. A 2l-He hybrid cryostat with 5 days holdtime for a 690 GHz InSb-bolometer

    NASA Astrophysics Data System (ADS)

    Woestenburg, E. E. M.; Casse, J. L.

    The design and construction of a 2-liter helium cryostat are described, using a closed cycle refrigerator to cool the cryostat radiation shields. A 5-day hold-time at 4.2 K has been achieved with this configuration. The cryostat is being used to cool a Schottky diode mixer at 350 GHz and an InSb bolometer at 690 GHz to 20 K and 4.2 K, respectively. The heat load on the 4 K cold station has been minimized using a thermal model of the cryostat, partly developed on the basis of measurements on the real cryostat. Using the model, insight was gained into the importance of various heat loads, permitting improvements in the original cryostat.

  3. Discovery of a Similar to 5 Day Characteristic Timescale in the Kepler Power Spectrum of Zw 229-15

    NASA Technical Reports Server (NTRS)

    Edelson, R.; Vaughan, S.; Malkan, M.; Kelly, B. C.; Smith, K. L.; Boyd, P. T.; Mushotzky, R.

    2014-01-01

    We present time series analyses of the full Kepler dataset of Zw 229- 15. This Kepler light curve- with a baseline greater than three years, composed of virtually continuous, evenly sampled 30-minute measurements - is unprecedented in its quality and precision. We utilize two methods of power spectral analysis to investigate the optical variability and search for evidence of a bend frequency associated with a characteristic optical variability timescale. Each method yields similar results. The first interpolates across data gaps to use the standard Fourier periodogram. The second, using the CARMA-based time-domain modeling technique of Kelly et al., does not need evenly-sampled data. Both methods find excess power at high frequencies that may be due to Kepler instrumental effects. More importantly both also show strong bends (delta alpha is approx. 2) at timescales of approx. 5 days, a feature similar to those seen in the X-ray PSDs of AGN but never before in the optical. This observed approx. 5 day timescale may be associated with one of several physical processes potentially responsible for the variability. A plausible association could be made with light -crossing, dynamical or thermal timescales, depending on the assumed value of the accretion disk size and on unobserved disk parameters such as alpha and H¬R. This timescale is not consistent with the viscous timescale, which would be years in a approx. 10(exp7) solar mass AGN such as Zw 229- 15. However there must be a second bend on long (& 1 year) timescales, and that feature could be associated with the viscous timescale.

  4. Discovery of a ∼5 day characteristic timescale in the Kepler power spectrum of Zw 229–15

    SciTech Connect

    Edelson, R.; Smith, K. L.; Mushotzky, R.; Vaughan, S.; Malkan, M.; Kelly, B. C.; Boyd, P. T.

    2014-11-01

    We present time series analyses of the full Kepler data set of Zw 229–15. This Kepler light curve—with a baseline greater than 3 yr, composed of virtually continuous, evenly sampled 30 minute measurements—is unprecedented in its quality and precision. We utilize two methods of power spectral analysis to investigate the optical variability and search for evidence of a bend frequency associated with a characteristic optical variability timescale. Each method yields similar results. The first interpolates across data gaps to use the standard Fourier periodogram. The second, using the CARMA-based time-domain modeling technique of Kelly et al., does not need evenly sampled data. Both methods find excess power at high frequencies that may be due to Kepler instrumental effects. More importantly, both also show strong bends (Δα ∼ 2) at timescales of ∼5 days, a feature similar to those seen in the X-ray power spectral densities of active galactic nuclei (AGNs) but never before in the optical. This observed ∼5 day timescale may be associated with one of several physical processes potentially responsible for the variability. A plausible association could be made with light-crossing dynamical or thermal timescales depending on the assumed value of the accretion disk size and on unobserved disk parameters such as α and H/R. This timescale is not consistent with the viscous timescale, which would be years in a ∼10{sup 7} M {sub ☉} AGN such as Zw 229–15. However, there must be a second bend on long (≳ 1 yr) timescales and that feature could be associated with the viscous timescale.

  5. Mean winds, temperatures and the 16- and 5-day planetary waves in the mesosphere and lower thermosphere over Bear Lake Observatory (42° N 111° W)

    NASA Astrophysics Data System (ADS)

    Day, K. A.; Taylor, M. J.; Mitchell, N. J.

    2011-11-01

    Atmospheric temperatures and winds in the mesosphere and lower thermosphere have been measured simultaneously using the Aura satellite and a meteor radar at Bear Lake Observatory (42° N, 111° W). The data presented in this study is from the interval March 2008 to July 2011. The mean winds observed in the summer-time over Bear Lake Observatory show the meridional winds to be equatorward at all heights during April-August and to reach monthly-mean speeds of -12 ms-1. The mean winds are closely related to temperatures in this region of the atmosphere and in the summer the coldest mesospheric temperatures occur about two weeks after the strongest equatorward meridional winds. In other seasons the meridional winds are poleward, reaching monthly-mean values of up to 12 ms-1. The zonal winds are eastward through most of the year and in the summer strong eastward zonal wind shears of up to ~4.5 ms-1 km-1 are present. However, westward winds are observed at the upper heights in winter and sometimes during the equinoxes. Considerable inter-annual variability is observed in the mean winds and temperatures. Comparisons of the observed winds with URAP and HWM-07 reveal some significant differences. Our radar zonal wind observations are generally more weakly eastward than these predicted by the URAP model zonal winds. Considering the radar meridional winds, in comparison to the HWM-07 our observations reveal equatorward flow at all heights in the summer whereas HWM-07 suggests that only weakly equatorward, or even poleward, flows occur at the lower heights. However, the zonal winds observed by the radar and modelled by HWM-07 are generally similar in structure and strength. Signatures of the 16- and 5-day planetary waves are clearly evident in both the radar-wind data and Aura-temperature. Short-lived wave events can reach large amplitudes of up to ~15 ms-1 and 8 K and 20 ms-1 and 10 K for the 16- and 5-day wave, respectively. A clear seasonal and short-term variability are

  6. Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats.

    PubMed

    Dunnick, June K; Shockley, Keith R; Morgan, Daniel L; Brix, Amy; Travlos, Gregory S; Gerrish, Kevin; Michael Sanders, J; Ton, T V; Pandiri, Arun R

    2017-04-01

    N,N-dimethyl-p-toluidine (DMPT), an accelerant for methyl methacrylate monomers in medical devices, was a liver carcinogen in male and female F344/N rats and B6C3F1 mice in a 2-year oral exposure study. p-Toluidine, a structurally related chemical, was a liver carcinogen in mice but not in rats in an 18-month feed exposure study. In this current study, liver transcriptomic data were used to characterize mechanisms in DMPT and p-toluidine liver toxicity and for conducting benchmark dose (BMD) analysis. Male F344/N rats were exposed orally to DMPT or p-toluidine (0, 1, 6, 20, 60 or 120 mg/kg/day) for 5 days. The liver was examined for lesions and transcriptomic alterations. Both chemicals caused mild hepatic toxicity at 60 and 120 mg/kg and dose-related transcriptomic alterations in the liver. There were 511 liver transcripts differentially expressed for DMPT and 354 for p-toluidine at 120 mg/kg/day (false discovery rate threshold of 5 %). The liver transcriptomic alterations were characteristic of an anti-oxidative damage response (activation of the Nrf2 pathway) and hepatic toxicity. The top cellular processes in gene ontology (GO) categories altered in livers exposed to DMPT or p-toluidine were used for BMD calculations. The lower confidence bound benchmark doses for these chemicals were 2 mg/kg/day for DMPT and 7 mg/kg/day for p-toluidine. These studies show the promise of using 5-day target organ transcriptomic data to identify chemical-induced molecular changes that can serve as markers for preliminary toxicity risk assessment.

  7. Lipid droplet dynamics and insulin sensitivity upon a 5-day high-fat diet in Caucasians and South Asians.

    PubMed

    Gemmink, Anne; Bakker, Leontine E H; Guigas, Bruno; Kornips, Esther; Schaart, Gert; Meinders, A Edo; Jazet, Ingrid M; Hesselink, Matthijs K C

    2017-02-14

    A 5-day High-Fat High-Calorie diet (HFHC-diet) reduces insulin-stimulated glucose disposal (Rd) in South Asian, but not Caucasian healthy lean males. We aimed to investigate if differences in myocellular lipid handling are underlying this differential response. A two-step hyperinsulinemic-euglycemic clamp and muscle biopsies were performed in 12 healthy lean Caucasian and South Asian males (BMI < 25 kg/m(2), 19-25 years) before and after a 5-day HFHC-diet (regular diet + 375 mL cream/day; 1275 kcal/day; 94% fat). Triglyceride extractions and Western Blots for lipid droplet and mitochondrial proteins were performed. Intramyocellular lipid content and HFHC-diet response were similar between ethnicities (group effect: P = 0.094; diet effect: +~30%, P = 0.044). PLIN5 protein content increased upon the HFHC-diet (P = 0.031) and tended to be higher in South Asians (0.87 ± 0.42 AU vs. 1.35 ± 0.58 AU, P = 0.07). 4-HNE tended to increase in South Asians upon the HFHC-diet (interaction effect: P = 0.057). In Caucasians ΔPLIN5 content correlated with ΔRd (Caucasians: r = 0.756, P = 0.011; South Asians: r = -0.085, P = 0.816), while in South Asians Δ4-HNE associated with ΔPLIN5 content (Caucasians: r = 0.312, P = 0.380; South Asians: r = 0.771, P = 0.003). These data indicate that in Caucasians, PLIN5 may be protective against HFHC-diet induced insulin resistance, which for reasons not yet understood is not observed in South Asians, who possess increased lipid peroxidation levels.

  8. Lipid droplet dynamics and insulin sensitivity upon a 5-day high-fat diet in Caucasians and South Asians

    PubMed Central

    Gemmink, Anne; Bakker, Leontine E. H.; Guigas, Bruno; Kornips, Esther; Schaart, Gert; Meinders, A. Edo; Jazet, Ingrid M.; Hesselink, Matthijs K. C.

    2017-01-01

    A 5-day High-Fat High-Calorie diet (HFHC-diet) reduces insulin-stimulated glucose disposal (Rd) in South Asian, but not Caucasian healthy lean males. We aimed to investigate if differences in myocellular lipid handling are underlying this differential response. A two-step hyperinsulinemic-euglycemic clamp and muscle biopsies were performed in 12 healthy lean Caucasian and South Asian males (BMI < 25 kg/m2, 19–25 years) before and after a 5-day HFHC-diet (regular diet + 375 mL cream/day; 1275 kcal/day; 94% fat). Triglyceride extractions and Western Blots for lipid droplet and mitochondrial proteins were performed. Intramyocellular lipid content and HFHC-diet response were similar between ethnicities (group effect: P = 0.094; diet effect: +~30%, P = 0.044). PLIN5 protein content increased upon the HFHC-diet (P = 0.031) and tended to be higher in South Asians (0.87 ± 0.42 AU vs. 1.35 ± 0.58 AU, P = 0.07). 4-HNE tended to increase in South Asians upon the HFHC-diet (interaction effect: P = 0.057). In Caucasians ΔPLIN5 content correlated with ΔRd (Caucasians: r = 0.756, P = 0.011; South Asians: r = −0.085, P = 0.816), while in South Asians Δ4-HNE associated with ΔPLIN5 content (Caucasians: r = 0.312, P = 0.380; South Asians: r = 0.771, P = 0.003). These data indicate that in Caucasians, PLIN5 may be protective against HFHC-diet induced insulin resistance, which for reasons not yet understood is not observed in South Asians, who possess increased lipid peroxidation levels. PMID:28195217

  9. The 27-day versus 13.5-day variations in the solar Lyman-alpha radiation and the radio wave absorption in the lower ionosphere over Europe

    NASA Technical Reports Server (NTRS)

    Delamorena, B. A.; Lastovicka, Jan; Rapoport, Z. TS.; Alberca, L.

    1989-01-01

    In order to clarify the question of solar periods in absorption, the pattern was studied of the solar Lyman-alpha radiation (the principal ionizing agent of the lower ionosphere) and of the radio wave absorption at five widely spaced places in Europe. When the solar Lyman-alpha flux variability is very well developed, then it dominates in the lower ionospheric variability. The most pronounced Lyman-alpha variation on time scale day-month is the solar rotation variation (about 27 days). When the Lyman-alpha variability is developed rather poorly, as it is typical for periods dominated by the 13.5 day variability, then the lower ionospheric variability appears to be dominated by variations of meteorological origin. The conclusions hold for all five widely spaced placed in Europe.

  10. Prenatal exposure to ethanol during late gestation facilitates operant self-administration of the drug in 5-day-old rats

    PubMed Central

    Miranda-Morales, Roberto Sebastián; Nizhnikov, Michael E.; Spear, Norman E.

    2014-01-01

    Prenatal ethanol exposure modifies postnatal affinity to the drug, increasing the probability of ethanol use and abuse. The present study tested developing rats (5-day-old) in a novel operant technique to assess the degree of ethanol self-administration as a result of prenatal exposure to low ethanol doses during late gestation. On a single occasion during each of gestational days 17–20, pregnant rats were intragastrically administered ethanol 1 g/kg, or water (vehicle). On postnatal day 5, pups were tested on a novel operant conditioning procedure in which they learned to touch a sensor to obtain 0.1% saccharin, 3% ethanol, or 5% ethanol. Immediately after a 15-min training session, a 6-min extinction session was given in which operant behavior had no consequence. Pups were positioned on a smooth surface and had access to a touch-sensitive sensor. Physical contact with the sensor activated an infusion pump, which served to deliver an intraoral solution as reinforcement (Paired group). A Yoked control animal evaluated at the same time received the reinforcer when its corresponding Paired pup touched the sensor. Operant behavior to gain access to 3% ethanol was facilitated by prenatal exposure to ethanol during late gestation. In contrast, operant learning reflecting ethanol reinforcement did not occur in control animals prenatally exposed to water only. Similarly, saccharin reinforcement was not affected by prenatal ethanol exposure. These results suggest that in 5-day-old rats, prenatal exposure to a low ethanol dose facilitates operant learning reinforced by intraoral administration of a low-concentration ethanol solution. This emphasizes the importance of intrauterine experiences with ethanol in later susceptibility to drug reinforcement. The present operant conditioning technique represents an alternative tool to assess self-administration and seeking behavior during early stages of development. PMID:24355072

  11. One session of high-intensity interval training (HIIT) every 5 days, improves muscle power but not static balance in lifelong sedentary ageing men

    PubMed Central

    Sculthorpe, Nicholas F.; Herbert, Peter; Grace, Fergal

    2017-01-01

    Abstract Background: Declining muscle power during advancing age predicts falls and loss of independence. High-intensity interval training (HIIT) may improve muscle power, but remains largely unstudied in ageing participants. Methods: This randomized controlled trial (RCT) investigated the efficacy of a low-frequency HIIT (LfHIIT) intervention on peak muscle power (peak power output [PPO]), body composition, and balance in lifelong sedentary but otherwise healthy males. Methods: Thirty-three lifelong sedentary ageing men were randomly assigned to either intervention (INT; n = 22, age 62.3 ± 4.1 years) or control (n = 11, age 61.6 ± 5.0 years) who were both assessed at 3 distinct measurement points (phase A), after 6 weeks of conditioning exercise (phase B), and after 6 weeks of HIIT once every 5 days in INT (phase C), where control remained inactive throughout the study. Results: Static balance remained unaffected, and both absolute and relative PPO were not different between groups at phases A or B, but increased significantly in INT after LfHIIT (P < 0.01). Lean body mass displayed a significant interaction (P < 0.01) due to an increase in INT between phases B and C (P < 0.05). Conclusions: 6 weeks of LfHIIT exercise feasible and effective method to induce clinically relevant improvements in absolute and relative PPO, but does not improve static balance in sedentary ageing men. PMID:28178145

  12. Continuing assessment of the 5 day sodium carbonate-ammonium nitrate extraction assay as an indicator test for silicon fertilizers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The five day sodium carbonate-ammonium nitrate extraction assay has been proposed by the AAFPCO as a standard test to identify fertilizers that provide plant-available Si. A single-lab validation test was previously performed; however, the analysis lacked any correlation to a grow-out study. To do...

  13. Fertility of Holstein heifers after two doses of PGF2α in 5-day CO-Synch progesterone-based synchronization protocol.

    PubMed

    Say, Erkan; Çoban, Serdal; Nak, Yavuz; Nak, Deniz; Kara, Uğur; White, Stephanie; Kasimanickam, Vanmathy; Kasimanickam, Ramanathan

    2016-09-01

    The objective of the study was to determine the effect of three different PGF2α (PGF) treatments in the 5-day CO-Synch progesterone-based synchronization protocol on artificial insemination (AI) pregnancy rate (PR) in Holstein heifers in Turkey and the United States. We hypothesized that two doses of PGF administered concurrently or 6 hours apart would result in greater AI pregnancy compared with a single dose of PGF on Day 5 at controlled internal drug release (CIDR) removal. In Turkey, Holstein heifers (n = 450) from one farm in the province of Adana and another farm in the province of Bursa were included. In the US, Holstein heifers (n = 483) from two locations in the state of Idaho were included. Heifers within locations were randomly allocated to one of three protocol groups: 1PGF-received 25 mg IM of dinoprost at CIDR removal; 2Co-PGF-received 50 mg IM of dinoprost at CIDR removal, and 2PGF-received 25 mg IM of dinoprost at CIDR removal and an additional 25 mg IM of dinoprost 6 hours later. All heifers received a CIDR (1.38 g of progesterone) and GnRH (10 μg IM of Buserelin [Turkey] or gonadorelin hydrochloride [US]) on Day 0. The CIDRs were removed on Day 5, and each heifer was given PGF according to the assigned treatments. On Day 7, each heifer was given another dose of GnRH and concurrently inseminated at 56 hours after CIDR removal. Heifers in both experiments were examined for pregnancy status between 35 and 45 days after AI. Overall, controlling for age, the heifers in the 2PGF group had greater AI-PR (61.7% [192/311]) than heifers in 2Co-PGF (48.2% [149/309]; P < 0.001) or 1PGF (53.7% [168/313]; P < 0.05) groups. No difference was observed between 2Co-PGF and 1PGF groups (P > 0.1). In Turkey, the heifers in the 2PGF group had a greater AI-PR (60% [90/150]) than 2Co-PGF (45.3% (68/150); P < 0.01] group. No difference was observed between 2PGF and 1PGF (55.3% [83/150]) groups (P > 0.1). There was a trend for AI pregnancy between 1

  14. Metabolic Response of Visceral White Adipose Tissue of Obese Mice Exposed for 5 Days to Human Room Temperature Compared to Mouse Thermoneutrality

    PubMed Central

    van der Stelt, Inge; Hoevenaars, Femke; Široká, Jitka; de Ronde, Lidwien; Friedecký, David; Keijer, Jaap; van Schothorst, Evert

    2017-01-01

    Housing of laboratory mice at room temperature (22°C) might be considered a constant cold stress, which induces a thermogenic program in brown adipose tissue (BAT). However, the early adaptive response of white adipose tissue (WAT), the fat storage organ of the body, to a change from thermoneutrality to room temperature is not known. This was investigated here for various WAT depots, focusing on epididymal WAT (eWAT), widely used as reference depot. Male adult diet-induced obese (DIO) C57BL/6JOlaHsd mice housed at thermoneutrality (29°C), were for 5 days either switched to room temperature (22°C) or remained at thermoneutrality. Energy metabolism was continuously measured using indirect calorimetry. At the end of the study, serum metabolomics and WAT transcriptomics were performed. We confirmed activation of the thermogenic program in 22°C housed mice. Body weight and total fat mass were reduced. Whole body energy expenditure (EE) was increased, with a higher fatty acid to carbohydrate oxidation ratio and increased serum acylcarnitine levels, while energy intake was not significantly different between the two groups. Transcriptome analysis of eWAT identified tissue remodeling and inflammation as the most affected processes. Expression of pro-inflammatory M1 macrophage-related genes, and M1 over M2 macrophage ratio were decreased, which might be linked to an increased insulin sensitivity. Markers of thermogenesis were not altered in eWAT. Decreased expression of tryptophan hydroxylase 2 (Tph2) and cholecystokinin (Cck) might represent altered neuroendocrine signaling. eWAT itself does not show increased fatty acid oxidation. The three measured WATs, epididymal, mesenteric, and retroperitoneal, showed mainly similar responses; reduced inflammation (s100a8), decreased carbohydrate oxidation, and no or small differences in fatty acid oxidation. However, Ucp1 was only expressed and increased in rWAT in 22°C housed mice. Cck expression was decreased in the three

  15. [Structural and functional organization of the vestibular apparatus in rats maintained under weightless conditions for 19.5 days aboard the satellite "Cosmos-782"].

    PubMed

    Vinnikov, Ia A; Gazenko, O G; Titova, L K; Bronshteĭn, A A; Govardovskiĭ, V I

    1978-01-01

    Vestibular apparatus was investigated in rats subjected to weightlessness for 19.5 days in the satelite "Cosmos-782" and experienced acceleration on launching and landing. Some structural and functional changes were noted. They were seen in otolith clinging to the utricular receptor surface and in the peripheral arrangement of the nucleolus in the nuclei of the receptor cells. It is also possible that increased edema of the vestibular tissue resulted in destruction of some receptor cells, and within the otolith--changes in the form and structure of otoconia. In the horizontal crista the cupula was separated.

  16. Structural and Functional Organization of the Vestibular Apparatus in Rats Subjected to Weightlessness for 19.5 Days Aboard the Kosmos-782 Satellite

    NASA Technical Reports Server (NTRS)

    Vinnikov, Y. A.; Gazenko, O. G.; Titova, L. K.; Bronshteyn, A. A.; Govardovskiy, V. I.; Pevzner, R. A.; Gribakin, G. G.; Aronova, M. Z.; Kharkeyevich, T. A.; Tsirulis, T. P.

    1978-01-01

    The vestibular apparatus was investigated in rats subjected to weightlessness for 19.5 days. The vestibular apparatus was removed and its sections were fixed in a glutaraldehyde solution for investigation by light and electron microscopes. Structural and functional charges were noted in the otolith portions of the ear, with the otolith particles clinging to the utricular receptor surface and with the peripheral arrangement of the nucleolus in the nuclei of the receptor cells. It is possible that increased edema of the vestibular tissue resulted in the destruction of some receptor cells and in changes in the form and structure of the otolith. In the horizontal crista, the capula was separated.

  17. Emergence of multipotent hemopoietic cells in the yolk sac and paraaortic splanchnopleura in mouse embryos, beginning at 8.5 days postcoitus.

    PubMed Central

    Godin, I; Dieterlen-Lièvre, F; Cumano, A

    1995-01-01

    We show by an in vitro approach that multipotent hemopoietic cells can be detected in the body of the mouse embryo between the stages of 10-25 somites (8.5-9.5 days of gestation)--i.e., prior to liver colonization (28-32 pairs of somites). Interestingly, hemopoietic cells appear in parallel in this location, the paraaortic splanchnopleura, and in the yolk sac, where they represent a new generation by reference to the primitive hemopoietic stem cells. Lymphoid cell clones, which could differentiate into mature B cells, were obtained from yolk sac and paraaortic splanchnopleura cell preparations but not from other tissues of the embryonic body. These B-cell precursors were first detected around the stage of 10 somites; thereafter, their initial minute numbers increased in parallel in the yolk sac and the paraaortic splanchnopleura, suggesting that their emergence in the two sites was simultaneous. By single cell manipulation, we show that these precursors can generate B and T lymphocytes and myeloid cells; these precursors can thus be defined as multipotent hemopoietic cells. Images Fig. 1 Fig. 4 PMID:7846049

  18. [Antibiotic therapy against acute tonsillopharyngitis in children due to group A beta-hemolytic streptococci: comparison of clinical efficacy, the bactericidal effects, and effects on oral flora between cefditoren pivoxil for 5 days and amoxicillin for 10 days].

    PubMed

    Tsumura, Naoki; Nagai, Kensuke; Hidaka, Hidenobu; Otsu, Yasushi; Tanaka, Yuhei; Ikezawa, Shigeru; Honma, Shinichi; Shindo, Shizuo; Ubukata, Kimiko

    2011-06-01

    We compared the clinical efficacy, the bactericidal effects, effect on the oral microbial flora, and adverse reactions between cefditoren pivoxil (CDTR-PI) for 5 days and amoxicillin (AMPC) for 10 days in children with acute group A beta-hemolytic streptococci (GAS) tonsillopharyngitis, and simultaneously examined the emm genotype and drug susceptibility of the isolated GAS. The results showed that the clinical efficacy was 100% for CDTR-PI and 97.9% for AMPC, with no difference between the two groups, and the bacterial elimination rate was 100% in both groups. No serious adverse event was noted in either group. On the other hand, concerning changes in the oral microbial flora between before and after treatment, the amount of bacteria showed no change in the CDTR-PI group (p = 0.5761) but clearly decreased in the AMPC group (p = 0.0049). This indicates that CDTR-PI does not disturb the oral microbial flora compared with AMPC. Also, the emm types determined in the 112 GAS strains isolated in this study were similar to those that have recently been isolated frequently in Japan. Concerning the drug resistance, none of the isolates showed resistance to beta-lactam antibiotics, but 45% of them were resistant to macrolides. The advantages of short-term treatment are considered to include a lower cost, improvement in drug compliance, decrease in the frequency of the occurrence of adverse reactions, decrease in the frequency of the appearance of drug-resistant strains, and alleviation of the psychological burden of patients and their parents. For these reasons, we conclude that CDTR-PI for 5 days is a useful option for the treatment of acute GAS tonsillopharyngitis in children.

  19. Comparison of follicular dynamics and hormone concentrations between the 7-day and 5-day CO-Synch + CIDR program in primiparous beef cows.

    PubMed

    Bridges, G A; Mussard, M L; Helser, L A; Day, M L

    2014-03-01

    The objectives were to compare follicular dynamics, preovulatory estradiol concentrations, and progesterone concentrations between the 7-day (7CO, n = 15) and 5-day (5CO, n = 13) CO-Synch + controlled internal drug release device (CIDR) program in primiparous suckled beef cows. On Day -7 (7CO) or Day -5 (5CO), GnRH (100 μg) was administered (GnRH-1) and a CIDR was inserted. On Day 0, hour 0, CIDR was removed and cows received PGF2α (25 mg) at hours 0 and 12. Animals were administered GnRH (100 μg, GnRH-2) at either hour 60 (7CO) or 72 (5CO). Follicular growth and ovulation to both GnRH-1 and GnRH-2 were evaluated using ultrasonography. Concentrations of estradiol were determined in blood samples taken at hours 0, 36, 60, and 72 (5CO). Blood samples were collected on Days 5, 8, and 14 for progesterone quantification. Ovulation rate to GnRH-1 did not differ between the 7CO (11/15) and 5CO (8/13) treatments, and for all dependent variables the statistical model included treatment, ovulation to GnRH-1, and their interaction. Diameter (mm) of the ovulatory follicle did not differ between treatments (13.4 ± 0.3) but was greater (P < 0.05) in cows that responded to GnRH-1 (13.8 ± 0.3) than those did not (12.6 ± 0.6). Maximum estradiol concentrations tended (P = 0.06) to be greater in the 5CO (7.3 ± 0.5 pg/mL) than 7CO (6.1 ± 0.7 pg/mL) treatment and tended to be greater (P = 0.08) in cows that responded to GnRH-1 (7.1 ± 0.5 pg/mL) than those did not (5.6 ± 0.9 pg/mL). Three cows in the 7CO treatment failed to develop a CL after GnRH-2. There was a treatment by response to GnRH-1 interaction (P < 0.05) for progesterone concentrations. In cows that did not respond to GnRH-1 in the 7CO treatment, progesterone concentrations were less (P < 0.05) than in those that responded to GnRH-1 in the 7CO treatment and tended (P = 0.09) to be less than in cows in the 5CO treatment that did not respond to GnRH-1. In conclusion, these findings demonstrate that failure to

  20. Decontamination efficacy of erbium:yttrium-aluminium-garnet and diode laser light on oral Candida albicans isolates of a 5-day in vitro biofilm model.

    PubMed

    Sennhenn-Kirchner, Sabine; Schwarz, Peter; Schliephake, Henning; Konietschke, Frank; Brunner, Edgar; Borg-von Zepelin, Margarete

    2009-05-01

    The different forms of superficial and systemic candidiasis are often associated with biofilm formation on surfaces of host tissues or medical devices. The biofilm formation of Candida spp., in general, necessitates significantly increased amounts of antifungal agents for therapy. Often the therapeutic effect is doubtful. A 5-day biofilm model with oral Candida isolates was established according to Chandra et al. (J Dent Res 80:903-908, 2001) on glass and titanium surfaces and was modified by Sennhenn-Kirchner et al. (Z Zahnärztl Implantol 3:45-51, 2007) to investigate different aspects unanswered in the field of dentistry. In this model, the efficacy of erbium:yttrium-aluminium-garnet (Er:YAG) light (2940 nm, 100 mJ, 10 Hz, 300 micros pulsed mode applied for 80 s) and diode laser light (810 nm, 1 W, continuous wave mode applied for 20 s with four repetitions after 30 s pauses each) was evaluated and compared to untreated controls. The photometric evaluation of the samples was completed by observations on morphological changes of yeast cells grown in the biofilm. Compared to the untreated controls Candida cells grown in mature in vitro biofilms were significantly reduced by both wavelengths investigated. Comparison between the different methods of laser treatment additionally revealed a significantly greater effect of the Er:YAG over the diode laser. Scanning electron microscopy findings proved that the diode laser light was effective in direct contact mode. In contrast, in the areas without direct contact, the fungal cells were left almost unchanged. The Er:YAG laser damaged the fungal cells to a great extent wherever it was applied.

  1. Reduced mydriasis from repeated doses of tropicamide and cyclopentolate.

    PubMed

    McCormack, D L

    1990-07-01

    Pupils are often dilated for examination the day before surgery and again on the day of surgery. The following experiment was performed to determine the effect of serial doses of two commonly used mydriatic agents: on two consecutive days the pupil of one of the eyes of 28 subjects was dilated with tropicamide 1%, and the pupil of one of the eyes of 30 subjects was dilated with cyclopentolate hydrochloride 1%. The other eyes in both groups were dilated only on the second day, and thus served as controls. Pupil sizes were measured from photographs before and after dilation. The pupils of the eyes treated twice with either drug did not dilate as well after the second dose as those of the control eyes (P less than .005 for tropicamide, P less than .001 for cyclopentolate). The pupils of the eyes twice-treated with tropicamide were an average of 0.15 mm smaller than the control pupils; those twice-treated with cyclopentolate were 0.36 mm smaller. For subjects treated with cyclopentolate, this decreased mydriasis was related to age (P less than .05) and to eye color (P less than .025): the younger and blue-eyed subjects dilated less on the second day than the older and brown-eyed subjects. If full mydriasis is required at surgery, pupils should probably not be dilated with either tropicamide or cyclopentolate the day before surgery.

  2. Modeling Single and Repeated Dose Pharmacokinetics of PFOA in Mice

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) displays complicated pharmacokinetics in that plasma serum concentration indicates a long half life – 3.8 years in humans (Olsen et al. 2007) – but also rapidly achieves steady-state (Lau et al., 2006). Attempts to address this have included using d...

  3. Pork meat increases iron absorption from a 5-day fully controlled diet when compared to a vegetarian diet with similar vitamin C and phytic acid content.

    PubMed

    Bach Kristensen, Mette; Hels, Ole; Morberg, Catrine; Marving, Jens; Bügel, Susanne; Tetens, Inge

    2005-07-01

    Meat increases absorption of non-haem iron in single-meal studies. The aim of the present study was to investigate, over a 5 d period, the potential increasing effect of consumption of pork meat in a whole diet on the fractional absorption of non-haem iron and the total absorption of iron, when compared to a vegetarian diet. A randomised cross-over design with 3 x 5 d whole-diet periods with diets containing Danish-produced meat, Polish-produced meat or a vegetarian diet was conducted. Nineteen healthy female subjects completed the study. All main meals in the meat diets contained 60 g of pork meat and all diets had high phytic acid content (1250 mumol/d). All main meals were extrinsically labelled with the radioactive isotope (59)Fe and absorption of iron was measured in a whole body counter. The non-haem iron absorption from the Danish meat diet was significantly higher compared to the vegetarian diet (P=0.031). The mean fractional absorption of non-haem iron was 7.9 (se1.1), 6.8 (se 1.0) and 5.3 (se 0.6) % for the Danish and Polish meat diets and vegetarian diet, respectively. Total absorption of iron was higher for both meat diets compared to the vegetarian diet (Danish meat diet: P=0.006, Polish meat diet: P=0.003). The absorption ratios of the present study were well in accordance with absorption ratios estimated using algorithms on iron bioavailability. Neither the meat diets nor the vegetarian diets fulfilled the estimated daily requirements of absorbed iron in spite of a meat intake of 180 g/d in the meat diets.

  4. Once-weekly and 5-days a week iron supplementation differentially affect cognitive function but not school performance in Thai children.

    PubMed

    Sungthong, Rassamee; Mo-suwan, Ladda; Chongsuvivatwong, Virasakdi; Geater, Alan F

    2004-09-01

    Many studies have reported comparable hemoglobin response in subjects given intermittent and daily iron supplements. However, the effect of intermittent iron supplementation on impaired cognitive function, one of the serious consequences of iron deficiency among children, has not been studied. We investigated the effects of 1 d/wk (weekly) and 5 d/wk (daily) iron supplementation on changes in results of intelligence quotient (IQ), Thai language, and mathematics tests among Thai primary schoolchildren. A double-blind, randomized, placebo-controlled trial was conducted. Primary schoolchildren (n = 397) were randomly assigned to receive iron supplements daily or weekly or placebo. Ferrous sulfate (300 mg) or placebo tablets were given under direct observation by the researcher for 16 wk. Changes in IQ, and Thai language and mathematics scores were then compared. The increases in hemoglobin concentration were comparable in the weekly and daily iron supplementation groups but serum ferritin increased more in the children supplemented daily. Children receiving daily iron supplements, however, had a significantly lower increase in IQ (3 +/- 12 points) than those receiving the supplement weekly (6 +/- 12 points) or placebo (6 +/- 12 points), whereas the last-mentioned two groups did not differ. Z-scores of Thai language and mathematics test results did not differ among the groups. We conclude that weekly iron supplementation is the regimen of choice in this study community.

  5. How are the physical and chemical properties of chrysotile asbestos altered by a 10-year residence in water and up to 5 days in simulated stomach acid

    SciTech Connect

    Seshan, K.

    1983-11-01

    Various tests and techniques were used to study the effect of exposure to simulated gastric juices as well as the effect of long term storage in water on asbestos fibers. Changes were noted in the physical, chemical and surface properties of chrysotile asbestos as a result of exposure to water, strong acids, and simulated gastric juices. The charge on the surface (the zeta potential) was changed from positive to negative; the surface became silica-like; and the magnesium was lost from the asbestos fibers on exposure to water and acid. The smaller the fiber diameter, the faster the loss of the magnesium. Notable among the changes in physical properties is a change in the refractive index. Asbestos exposed to acids or water may not be detectable using the dispersion staining techniques that identify asbestos based on the refractive index. Other physical property changes include the destruction of the gross crystallinity of the fibers. The x-ray diffraction signal disappears when fibers are exposed to acid. The fibers may still be detected by electron diffraction. Upon acid exposure, the magnesium ions are leached out, leaving a magnesium-free silica network. A positive ion, possibly the proton or the hydronium ion, replaces the lost magnesium ion. 20 references, 11 figures, 2 tables.

  6. Rapid acquisition of operant conditioning in 5-day-old rat pups: a new technique articulating suckling-related motor activity and milk reinforcement.

    PubMed

    Arias, Carlos; Spear, Norman E; Molina, Juan Carlos; Molina, Agustin; Molina, Juan Carlos

    2007-09-01

    Newborn rats are capable of obtaining milk by attaching to a surrogate nipple. During this procedure pups show a gradual increase in head and forelimb movements oriented towards the artificial device that are similar to those observed during nipple attachment. In the present study the probability of execution of these behaviors was analyzed as a function of their contingency with intraoral milk infusion using brief training procedures (15 min). Five-day-old pups were positioned in a smooth surface having access to a touch-sensitive sensor. Physical contact with the sensor activated an infusion pump which served to deliver intraoral milk reinforcement (Paired group). Yoked controls received the reinforcer when Paired neonates touched the sensor. Paired pups trained under a continuous reinforcement schedule emitted significantly more responses than Yoked controls following two (Experiment 1) or one training session (Experiment 2). These differences were also observed during an extinction session conducted immediately after training. The level of maternal deprivation before training (3 or 6 hr) or the volume of milk delivered (1.0 or 1.5 microl per pulse) did not affect acquisition or extinction performances. In addition, it was observed that the rate of responding of Paired pups during the early phase of the extinction session significantly predicted subsequent levels of acceptance of the reinforcer. These results indicate that the frequency of suckling-related behaviors can be rapidly modified by means of associative operant processes. The operant procedure here described represents an alternative tool for the ontogenetic analysis of self-administration or behavior processes of seeking.

  7. A 5-day method for determination of soluble silicon concentrations in nonliquid fertilizer materials using a sodium carbonate-ammonium nitrate extractant followed by visible spectroscopy with heteropoly blue analysis: single-laboratory validation.

    PubMed

    Sebastian, Dennis; Rodrigues, Hugh; Kinsey, Charles; Korndörfer, Gaspar; Pereira, Hamilton; Buck, Guilherme; Datnoff, Lawrence; Miranda, Stephen; Provance-Bowley, Mary

    2013-01-01

    A 5-day method for determining the soluble silicon (Si) concentrations in nonliquid fertilizer products was developed using a sodium carbonate (Na2CO3)-ammonium nitrate (NH4NO3) extractant followed by visible spectroscopy with heteropoly blue analysis at 660 nm. The 5-Day Na2CO3-NH4NO3 Soluble Si Extraction Method can be applied to quantify the plant-available Si in solid fertilizer products at levels ranging from 0.2 to 8.4% Si with an LOD of 0.06%, and LOQ of 0.20%. This Si extraction method for fertilizers correlates well with plant uptake of Si (r2 = 0.96 for a range of solid fertilizers) and is applicable to solid Si fertilizer products including blended products and beneficial substances. Fertilizer materials can be processed as received using commercially available laboratory chemicals and materials at ambient laboratory temperatures. The single-laboratory validation of the 5-Day Na2CO3-NH4NO3 Soluble Si Extraction Method has been approved by The Association of American Plant Food Control Officials for testing nonliquid Si fertilizer products.

  8. Nuclear criticality safety: 5-day training course

    SciTech Connect

    Schlesser, J.A.

    1992-11-01

    This compilation of notes is presented as a source reference for the criticality safety course. It represents the contributions of many people, particularly Tom McLaughlin, the course's primary instructor. At the completion of this training course, the attendee will: be able to define terms commonly used in nuclear criticality safety; be able to appreciate the fundamentals of nuclear criticality safety; be able to identify factors which affect nuclear criticality safety; be able to identify examples of criticality controls as used at Los Alamos; be able to identify examples of circumstances present during criticality accidents; be able to identify examples of computer codes used by the nuclear criticality safety specialist; be able to identify examples of safety consciousness required in nuclear criticality safety.

  9. Nuclear criticality safety: 5-day training course

    SciTech Connect

    Schlesser, J.A.

    1992-11-01

    This compilation of notes is presented as a source reference for the criticality safety course. It represents the contributions of many people, particularly Tom McLaughlin, the course`s primary instructor. At the completion of this training course, the attendee will: be able to define terms commonly used in nuclear criticality safety; be able to appreciate the fundamentals of nuclear criticality safety; be able to identify factors which affect nuclear criticality safety; be able to identify examples of criticality controls as used at Los Alamos; be able to identify examples of circumstances present during criticality accidents; be able to identify examples of computer codes used by the nuclear criticality safety specialist; be able to identify examples of safety consciousness required in nuclear criticality safety.

  10. Apollo Soyuz Mission: 5-Day Report

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The Apollo Soyuz Test Project mission objectives and technical investigations are summarized. Topics discussed include: spacecraft and crew systems performance; joint flight activities; scientific and applications experiments; in-flight demonstrations; biomedical considerations; and mission support performance.

  11. A 5-day cytoreductive chemotherapy followed by haplo-identical hsct (FA5-BUCY) as a tumor-ablative regimen improved the survival of patients with advanced hematological malignancies

    PubMed Central

    Chen, Ping; Yuan, Xiaohong; Luo, Xiaofeng; Liu, Tingbo; Zheng, Jing; Zheng, Zhihong; Zheng, Xiaoyun; Chen, Xinji; Zhang, Langhui; Zheng, Hao; Chen, Zaisheng; Hua, Xueling; Le, Shaohua; Li, Jian; Chen, Zhizhe; Hu, Jianda

    2016-01-01

    Haplo-HSCT has been used when HLA-matched siblings are not available. Conditioning regimens aim to reduce tumor burden prior to HSCT and provide sufficient immunoablation. We report the outcome of haplo-HSCT in 63 consecutive patients from 2/2013 to 12/2015 (19 females/44 males) with high-risk or relapsed/refractory hematological malignancies (n=29-AML; 8-sAML; 19-ALL; 5-advanced-MDS; 2-CML-BC). Median age was 20 years (range: 1.1-49). Twenty-one patients achieved remission prior to transplant, while 42 did not. Patients received FA5-BUCY, i.e., 5-day salvage chemotherapy (Fludarabine/Ara-C) and conditioning (Busulfan/Cyclophosphamide). GvHD prophylaxis included ATG, CsA, MMF and short-term MTX. All patients received stem cells from bone marrow and peripheral blood, and achieved successful engraftment, except two who died before. With a median follow-up of 269 days (120-1081), 42/63 patients are still alive and disease-free. Two-year OS and RFS were similar in patients not in remission and in those in complete remission (61.3% vs 56.3%, p=0.88; 58.3% vs 56.3%, p=0.991). Non-relapse mortality and relapse incidence were 22.2% and 11.1%, respectively. Severe acute-GvHD occurred in 4/63 patients. Transplant-related mortality was low at day+100 (17.5%) and for the entire study period (20.6%). Unexpectedly, few patients experienced mild-to-moderate toxicity, and main causes of death were infection and GvHD. BM blast counts, age, and donor-recipient gender-pairs did not affect the outcome. Less chemotherapy cycles prior to HSCT might result in more favorable outcome. Thus, haplo-HSCT with FA5-BUCY appears promising for advanced disease, especially when TBI and amsacrine, used for FLAMSA, are not available and in pediatric patients for whom TBI is not recommended. PMID:27705929

  12. Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics

    PubMed Central

    Li, Junfeng; Zhang, Zhaoyun; Liu, Xiaoxia; Wang, Yi; Mao, Fei; Mao, Junjun; Lu, Xiaolan; Jiang, Dongdong; Wan, Yun; Lv, Jia-Ying; Cao, Guoying; Zhang, Jing; Zhao, Naiqing; Atkinson, Mark; Greiner, Dale L.; Prud'homme, Gerald J.; Jiao, Zheng; Li, Yiming; Wang, Qinghua

    2015-01-01

    Preclinical studies show that GABA exerts anti-diabetic effects in rodent models of type 1 diabetes. Because little is known about its absorption and effects in humans, we investigated the pharmacokinetics and pharmacodynamics of GABA in healthy volunteers. Twelve subjects were subjected to an open-labeled, three-period trial involving sequential oral administration of placebo, 2 g GABA once, and 2 g GABA three times/day for 7 days, with a 7-day washout between each period. GABA was rapidly absorbed (Tmax: 0.5 ~ 1 h) with the half-life (t1/2) of 5 h. No accumulation was observed after repeated oral GABA administration for 7 days. Remarkably, GABA significantly increased circulating insulin levels in the subjects under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01). GABA also increased glucagon levels only under fasting conditions (1.3-fold, single dose, p < 0.05; 1.5-fold, repeated dose, p < 0.01). However, there were no significant differences in the insulin-to-glucagon ratio and no significant change in glucose levels in these healthy subjects during the study period. Importantly, GABA significantly decreased glycated albumin levels in the repeated dosing period. Subjects with repeated dosing showed an elevated incidence of minor adverse events in comparison to placebo or the single dosing period, most notably transient discomforts such as dizziness and sore throat. However, there were no serious adverse events observed throughout the study. Our data show that GABA is rapidly absorbed and tolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal secretion, suggest potential therapeutic benefits for diabetes. PMID:26617516

  13. Annual maximum 5-day rainfall total and maximum number of consecutive dry days over Central America and the Caribbean in the late twenty-first century projected by an atmospheric general circulation model with three different horizontal resolutions

    NASA Astrophysics Data System (ADS)

    Nakaegawa, T.; Kitoh, A.; Murakami, H.; Kusunoki, S.

    2014-04-01

    We simulated changes in annual maximum 5-day rainfall (RX5D) and annual maximum number of consecutive dry days (CDD) in Central America, Mexico, and the Caribbean with three different horizontal resolution atmospheric global general circulation models (AGCMs) and quantified the uncertainty of the projections. The RX5Ds and CDDs were projected to increase in most areas in response to global warming. However, consistent changes were confined to small areas: for RX5D, both coastal zones of northern Mexico and the Yucatan Peninsula; for CDD, the Pacific coastal zone of Mexico, the Yucatan Peninsula, and Guatemala. All three AGCMs projected that RX5Ds and CDDs averaged over only the land area and over the entire area (land and ocean) would increase. The dependence of RX5D probability density functions on the horizontal resolutions was complex. Precipitation unrelated to tropical cyclones was primarily responsible for the projected increases in the frequency of RX5Ds greater than 300 mm.

  14. Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart.

    PubMed

    Farré, Magí; Tomillero, Angels; Pérez-Mañá, Clara; Yubero, Samanta; Papaseit, Esther; Roset, Pere-Nolasc; Pujadas, Mitona; Torrens, Marta; Camí, Jordi; de la Torre, Rafael

    2015-10-01

    3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular psychostimulant, frequently associated with multiple administrations over a short period of time. Repeated administration of MDMA in experimental settings induces tolerance and metabolic inhibition. The aim is to determine the acute pharmacological effects and pharmacokinetics resulting from two consecutive 100mg doses of MDMA separated by 4h. Ten male volunteers participated in a randomized, double-blind, crossover, placebo-controlled trial. The four conditions were placebo plus placebo, placebo plus MDMA, MDMA plus placebo, and MDMA plus MDMA. Outcome variables included pharmacological effects and pharmacokinetic parameters. After a second dose of MDMA, most effects were similar to those after a single dose, despite a doubling of MDMA concentrations (except for systolic blood pressure and reaction time). After repeated MDMA administration, a 2-fold increase was observed in MDMA plasma concentrations. For a simple dose accumulation MDMA and MDA concentrations were higher (+23.1% Cmax and +17.1% AUC for MDMA and +14.2% Cmax and +10.3% AUC for MDA) and HMMA and HMA concentrations lower (-43.3% Cmax and -39.9% AUC for HMMA and -33.2% Cmax and -35.1% AUC for HMA) than expected, probably related to MDMA metabolic autoinhibition. Although MDMA concentrations doubled after the second dose, most pharmacological effects were similar or slightly higher in comparison to the single administration, except for systolic blood pressure and reaction time which were greater than predicted. The pharmacokinetic-effects relationship suggests that when MDMA is administered at a 4h interval there exists a phenomenon of acute tolerance to its effects.

  15. Efficacy and safety of pharmacokinetically enhanced amoxicillin-clavulanate at 2,000/125 milligrams twice daily for 5 days versus amoxicillin-clavulanate at 875/125 milligrams twice daily for 7 days in the treatment of acute exacerbations of chronic bronchitis.

    PubMed

    Sethi, Sanjay; Breton, John; Wynne, Brian

    2005-01-01

    This randomized, controlled trial was designed to show that a short, 5-day course of pharmacokinetically enhanced amoxicillin-clavulanate at 2,000/125 mg (Augmentin XR) is as effective clinically as a longer, 7-day course of conventional amoxicillin-clavulanate at 875/125 mg (both given twice daily) in the treatment of acute exacerbations of chronic bronchitis (AECB). Amoxicillin-clavulanate at 2,000/125 mg was designed to extend the therapeutic levels of amoxicillin in serum over the 12-h dosing interval, compared with conventional formulations, to eradicate bacterial strains for which amoxicillin MICs were < or =4 microg/ml while retaining efficacy against beta-lactamase-producing pathogens. A total of 893 patients were randomized and received study medication (amoxicillin-clavulanate at 2,000/125 mg for 443 patients and 875/125 mg for 450 patients). Overall, 141 patients receiving amoxicillin-clavulanate at 2,000/125 mg and 135 receiving the comparator formulation had at least one pathogen identified at screening. Amoxicillin-clavulanate at 2,000/125 mg was as effective clinically in the per-protocol (PP) population at the test of cure (days 14 to 21, primary efficacy endpoint) as amoxicillin-clavulanate at 875/125 mg (clinical success rates of 93.0 and 91.2%, respectively; treatment difference, 1.8; 95% confidence interval [CI], -2.2, 5.7). Bacteriological success in the bacteriology PP population was high for both formulations (amoxicillin-clavulanate at 2,000/125 mg, 76.7%; amoxicillin-clavulanate at 875/125 mg, 73.0%; treatment difference, 3.8; 95% CI, -7.5, 15.0). Both therapies were well tolerated, with a similar incidence of adverse events. Fewer than 5% of patients in each group withdrew from the study due to adverse events. The shorter, 5-day course of amoxicillin-clavulanate at 2,000/125 mg was shown to be as effective clinically as a longer, 7-day course of amoxicillin-clavulanate at 875/125 mg, with high bacteriological efficacy and no difference in

  16. Toxicological evaluation of peroxy sulfonated oleic acid (PSOA) in subacute and developmental toxicity studies.

    PubMed

    Pechacek, Nathan; Laidlaw, Karen; Clubb, Stephanie; Aulmann, Walter; Osorio, Magdalena; Caudill, Jeff

    2013-12-01

    Peroxy sulfonated oleic acid (PSOA) is a new coupler used in sanitizing solutions primarily for the food and beverage industry. The toxicity of PSOA was evaluated in a 28-day repeat dose study according to OECD 407 guidelines with a 14-day recovery period and a developmental toxicity study according to OECD 414 guidelines. In both studies, PSOA was administered once daily via gavage at 0, 5, 15 and 50 mg/kg/day to Sprague-Dawley rats. Due to its corrosive properties, the highest test concentration was restricted to 0.5%. No findings related to PSOA administration were observed for the 28-day repeat-dose study and the NOEL is 50 mg/kg/day. Additionally, no impairment of the mucous membranes of the gastrointestinal tract was observed up to 0.5%, which is considered the NOEC in terms of local toxicity. For the developmental study, an embryo-fetal NOEL of 50 mg/kg/day was identified and the maternal NOEL is considered to be 15 mg/kg/day, based on slight reductions in maternal body weight and food consumption, as well as a modest increase in the incidence of clinical observations at the high dose. These findings demonstrate that PSOA appears to have minimal potential to induce toxicity associated with repeat-dose or developmental exposures.

  17. [Twenty-eight-day repeated dose toxicity test for tetrachlorvinphos in Wistar rat].

    PubMed

    Ogawa, Y; Suzuki, S; Takada, K; Sai, K; Kamata, E; Umemura, T; Kaneko, T; Kurokawa, Y

    1990-01-01

    A 28-day oral toxicity test of tetrachlorvinphos (TCV) was conducted in male and female Slc: Wistar rats by gavage at dose levels of 0, 10, 100 or 1000 mg/kg/day. The male and female rats showed dose-related inhibition of serum cholinesterase activity and erythrocyte acetylcholinesterase activity. At a dose of 1000 mg/kg, body weight gain was decreased in males, and there were 6 deaths in females. Adrenal gland, liver, kidney and thyroid gland weights were increased. The adrenal lesions were characterized by vacuolization and swelling of the cortex cells. The hepatic lesions consisted of vacuolization and necrosis of the hepatocytes. The renal lesions consisted of regeneration and necrosis of the tubular epithelial cells. These lesions were mostly observed at a dose of 1000 mg/kg. After a 14-day recovery period in the 1000 mg/kg group, the changes of cholinesterase, total cholesterol, gamma-glutamyltransferase, alkaline phosphatase, aspartate aminotransferase and blood urea nitrogen in serum were restored or showed a tendency toward recovery. However, the lesions in the kidney and adrenal remained. More than 14 days are therefore considered to be needed for recovery. At doses of more than 10 mg/kg, significant inhibition of the serum cholinesterase activity in both sexes, erythrocyte acetylcholinesterase activity in males, and lesions of the adrenal gland in females were observed. Target organs for TCV-treated rats were the adrenal, liver and kidney. It was concluded that the NOEL under this experimental condition is less than 10 mg/kg/day.

  18. [Visual-manual tracking during 5-day dry immersion].

    PubMed

    Kornilova, L N; Naumov, I A; Glukhikh, D O

    2011-01-01

    Level dry immersion (DI), a model of the physiological effects of microgravity, support deprivation, minimization of muscle activity and proprioceptive afferentation specifically, was used to determine the effects of low proprioceptive, tactile and support afferentation on visual-manual tracking. Hand-eye motor coordination was tested in 13 subjects in 5-d DI who tracked jerky and smooth (linear and pendulum-like horizontal and vertical, circular clockwise and counterclockwise) motions of point visual stimulus. Binocular electrooculography was used to register ocular movements and a joystick with a biological visual feedback to register manual motor acts (1 of 2 stimuli on the screen showed the actual joystick inclination). Computerized stimulation was provided with the help of virtual goggles. Evaluated parameters were latent and total reaction time, amplitude and velocity of eye and hand movements, coefficients of effectiveness (amplitudes ratio) and gain (velocity ratio). Testing was performed before DI, after 3 hours in DI, on DI days 3 and 5, during the first hours and in 3 days after DI (all subjects) and on post-DI days 5-7 (4 subjects). It was demonstrated that support deprivation and minimization of proprioceptive afferentation affect ocular tracking to a larger degree than accuracy of the manual motor act of following the visual stimulus. Manual tracking by all subjects was found more accurate than visual and did not alter significantly during tests sessions; on the contrary, visual tracking accuracy altered noticeably as in the course, so after DI.

  19. Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis.

    PubMed

    Deterding, Robin; Retsch-Bogart, George; Milgram, Laura; Gibson, Ron; Daines, Cori; Zeitlin, Pamela L; Milla, Carlos; Marshall, Bruce; Lavange, Lisa; Engels, Jean; Mathews, Dave; Gorden, Joann; Schaberg, Amy; Williams, Judy; Ramsey, Bonnie

    2005-04-01

    Denufosol tetrasodium (INS37217) is a selective P2Y(2) agonist that stimulates ciliary beat frequency and Cl(-) secretion in normal and cystic fibrosis (CF) airway epithelia, and is being investigated as an inhaled treatment for CF. The Cl(-) secretory response is mediated via a non-CFTR pathway, and the driving force for Cl(-) secretion is enhanced by the effect of P2Y(2) activation to also inhibit epithelial Na(+) transport. Denufosol is metabolically more stable and better tolerated, and may enhance mucociliary clearance for a longer period of time than previously investigated P2Y(2) agonists. The goal of this phase 1/phase 2 study was to assess the safety and tolerability of single and repeated doses of aerosolized denufosol in subjects with CF. The study was a double-blind, placebo-controlled, multicenter comparison of ascending single doses of denufosol (10, 20, 40, and 60 mg, administered by inhalation via the Pari LC Star nebulizer) vs. placebo (normal saline), followed by a comparison of twice-daily administration of the maximum tolerated dose (MTD) of denufosol or placebo for 5 days. Thirty-seven adult (18 years of age or older) and 24 pediatric (5-17 years of age) subjects with CF were evaluated in five cohorts. Subjects were randomized in a 3:1 ratio to receive either denufosol or placebo within each cohort. The percent of subjects experiencing adverse events was similar between the denufosol and placebo groups. The most common adverse event in subjects receiving denufosol was chest tightness in adult subjects (39%) and cough in pediatric subjects (56%). Three (7%) subjects receiving denufosol and one (7%) subject receiving placebo experienced a serious adverse event. Forced expiratory volume in 1 sec (FEV(1)) profiles following dosing were similar across treatment groups, with some acute, reversible decline seen in both groups, most notably in subjects with lower lung function at baseline. In conclusion, doses up to 60 mg of denufosol inhalation

  20. Residual effect of single and repeated doses of midazolam and nitrazepam in relation to their plasma concentrations.

    PubMed

    Godtilbsen, O B; Jerkø, D; Gordeladze, J O; Bredesen, J E; Matheson, I

    1986-01-01

    Twelve healthy volunteers were given either midazolam 15 mg or nitrazepam 5 mg for 7 consecutive days in a randomized cross-over trial. Self-assessment of sleep, mood or condition on awakening and adverse effects was performed, and the volunteers underwent evaluation of psychomotor performance. Hypnotic effect, judged by the classical sleep variables, showed that the drugs were more or less equal and were superior to placebo. Nitrazepam consistently produced an impaired condition on awakening and also clearly displayed a spectrum of adverse motor effects. Motor tests revealed impairment induced by both drugs, but, in the midazolam group the effect subsided during the trial period. Both drugs had a significant effect on memory, midazolam appearing to perturb certain memory functions to a greater extent than did nitrazepam. The residual plasma concentration of midazolam 11 h after treatment correlated well with the scores obtained in several of the psychomotor tests, whereas plasma nitrazepam levels were not related to performance in any subtest. When discontinued neither drugs, induced any rebound phenomenon. However, the adverse effects of nitrazepam appeared to be carried over into the adjacent placebo period.

  1. 28-day repeated dose oral toxicity of human copper-zinc superoxide dismutase from recombinant Pichia pastori in rats.

    PubMed

    Zhu, Liang; Tian, Ying-Juan; Zhu, Si-Ming

    2012-04-01

    Human copper/zinc superoxide dismutase from recombinant Pichia pastori (RH-Cu/Zn-SOD) was orally administered, via gavage, to Sprague-Dawley rats at 500, 1,000, and 2,000 mg/kg body weight/day for 28 days. During the 28-day period, animals were examined for evidence of toxicity; there were no deaths, and in-life physical signs were normal. On day 29, the animals were exsanguinated, examined for gross pathology, and tissues were preserved for histopathology. Although statistical differences were noted in some hematology and clinical chemistry, they were of questionable biological significance. The results of the 28-day oral administration demonstrated a lack of toxicity of RH-Cu/Zn-SOD in rats. There were no treatment-related, toxicologically relevant changes in clinical signs, growth, food consumption, hematology, clinical chemistry, organ weights, or pathology. The no observed adverse effect level was greater than 2,000 mg/kg/day for RH-Cu/Zn-SOD in rats.

  2. Influence of a 3.5 Day Fast on Physical Performance Running Heading: Fasting and Performance,

    DTIC Science & Technology

    1986-01-01

    food has long...for consuming food and periods of nonsupply in remote areas. In these and other situations the metabolic changes that occur during the early stages of...the decrement in isokinetic strength was small. The absence of food for a period of a few days would seem to have little impact on voluntary

  3. [Direct proteome profiling of human blood serum in the experiment with 5-day dry immersion].

    PubMed

    Pastushkova, L Kh; Pakharukova, N A; Trifonova, O P; Dobrokhotov, I V; Valeeva, O A; Larina, I M

    2011-01-01

    Purpose of the investigation was to determine changes in blood plasma proteome in healthy human subjects (n = 14, 19 to 26 y.o.) in an experiment with dry immersion (DI). Plasma samples were drawn 7 and 2 days before the exposure, on DI days 2, 3 and 5, and on days 1, 3, 7 and 15 after the experiment. Previous to direct MALDI-TOF mass-spectrometric profiling, serum samples were pre-fractionated and enriched with magnetic particles MB WCX (WCX--a weak cation exchanger) on ClinProt (Bruker Daltonics). In each spectrum, 175 MS-peaks were detected on average within the mass range from 1000 to 17,000 Da with the signal/noise ratio = 5. Student's criterion (p < 0.05) was used to define reliable differences between DI and baseline samples from 48 peaks (27.4 % of all the proteome profile peaks). On DI days 2 and 3, growth of peak areas was observed in fragments of complement system proteins C3 and C4, high-molecular kininogen and fibrinogen that can be attributed to organism adaptation to conditions of the experiment. Significant increases of the peak area of apolipoprotein CI (reduced form with segregated threonine and proline) and C4 enzymes of the complement system, and fibrinogen on the first day after the experiment can be related to changes in motor activities of the subjects.

  4. [Renal functioning and human body liquids during 5-day dry immersion].

    PubMed

    Noskov, V B; Larina, I M; Pastushkova, L Kh; Dobrokhotov, I V; Valeeva, O A; Coupe, M; Custaud, M -A; Novoselova, A M

    2011-01-01

    Renal function and body composition, including liquids, were investigated in 14 essentially healthy male subjects during simulation of some spaceflight effects by 5-d dry immersion (DI). Noninvasive measurement of water spaces of organism was performed with the methods of bio-impedance analysis (BIA). Increase of renal excretion of liquids and appearance of negative water balance were observed. BIA revealed reductions of total body and extracellular liquids and a decrease of circulating plasma volume. This means, that DI induced hypohydration of organism. In the post-DI period, the hydration status regained its baseline level fairly soon. Lean body mass slightly decreased; adipose mass, on the contrary, exceeded baseline values. Moreover, the experiment evidenced technical impossibility to obtain valid impedansimetry data in DI.

  5. Poster 5: Day to night ion transport flow and its variation with SLT

    NASA Astrophysics Data System (ADS)

    Ma, Yingjuan; Nagy, Andy F.

    2016-06-01

    In this presentation, we will examine the day to night ion transport flow at Titan based on 3D MHD model results. As this flow is influenced by the relative direction of the upstream co-rotation plasma flow as Titan moved along its orbit, we will present and compare the day-to-night ion transport flow at four different SLTs.

  6. Comparative clinical pharmacokinetics of antibody-drug conjugates in first-in-human Phase 1 studies

    PubMed Central

    Deslandes, Antoine

    2014-01-01

    Although there are currently more than 30 antibody-drug conjugates (ADC) in clinical development for the treatment of blood cancers and solid tumors, comparison of their clinical pharmacokinetics (PK) is challenging because of the large number of, and differences between, the targets, ADC constructs, dosing regimens, and patient populations. In this review, we standardized the evaluation, using non-compartmental PK data reported at Cycle 1, i.e., following the first drug administration of what is usually a repeated-dose treatment, in monotherapy. We report ADC clinical PK properties, dosing regimen, determination of doses ranges and associated maximum tolerated doses. We also evaluated the effect of structural characteristics and target types (hematological vs. solid tumors) on PK. In addition, we discuss how integration of PK/pharmacodynamics approaches on top of classical dose escalation in first-in-human studies may improve dosing regimen determination for subsequent phases of clinical development. PMID:24852950

  7. Biodistribution of PLGA and PLGA/chitosan nanoparticles after repeat-dose oral delivery in F344 rats for 7 days

    PubMed Central

    Navarro, Sara M; Darensbourg, Caleb; Cross, Linda; Stout, Rhett; Coulon, Diana; Astete, Carlos E; Morgan, Timothy; Sabliov, Cristina M

    2015-01-01

    Aim To quantify in vivo the biodistribution of poly(lactic-co-glycolic) acid (PLGA) and PLGA/chitosan nanoparticles (PLGA/Chi NPs) and assess if the positive charge of chitosan significantly enhances nanoparticle absorption in the GI tract. Material & methods PLGA and PLGA/Chi NPs covalently linked to tetramethylrhodamine-5-isothiocyanate (TRITC) were orally administered to F344 rats for 7 days, and the biodistribution of fluorescent NPs was analyzed in different organs. Results The highest amount of particles (% total dose/g) was detected for both treatments in the spleen, followed by intestine and kidney, and then by liver, lung, heart and brain, with no significant difference between PLGA and PLGA/Chi NPs. Conclusion Only a small percentage of orally delivered NPs was detected in the analyzed organs. The positive charge conferred by chitosan was not sufficient to improve the absorption of the PLGA/Chi NPs over that of PLGA NPs. PMID:25491670

  8. Repeated-Dose and Reproductive/Developmental Toxicity of NTO (3-Nitro-1,2,4-Triazol-5-One) in the Rat

    DTIC Science & Technology

    2014-03-21

    cell count ( RBC ), hemoglobin (HGB), hematocrit (HCT), mean cell volume (MCV) , mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC...noted in all male and female dose groups. Although the severity of this lesion may intensify with chemical exposures, a few isolated aggregates of 14...OFP4-93-12.03.03 Ropeated-Ooae and Reproductlve/Oevelopmontal Toxicity ol NTO In the Ret Individual Hematology Results Male Reta BASO RBC HGB HCT

  9. Effects of D-004, a lipid extract of the fruit of the Cuban royal palm (Roystonea regia) or the lipidosterolic extract of saw palmetto (Serenoa repens) on the sexual activity in male rats: A controlled, experimental study

    PubMed Central

    Fernández, Lilia C.; Mas, Rosa; Fernández, Julio; Mendoza, Sarahí; Gámez, Rafael; Pardo, Balia

    2008-01-01

    Background: The etiology of benign prostatic hyperplasia (BPH) is not completely understood, but hormonal changes in aging men seem to be pivotal. Dihydrotestosterone, a potent, active metabolite of testosterone, is formed by the enzymatic action of prostate 5α-reductase and causes cell growth and hyperplasia. Consistent with this action, male sexual dysfunction has been clinically documented to be among the drug-related adverse events associated with 5α-reductase inhibitors. The lipidosterolic extract of saw palmetto (LESP) fruit (Serenoa repens) has been used to treat BPH. D-004, a lipid extract of Roystonea regia Royal palm fruit, has been found to prevent prostatic hyperplasia induced by testoste-rone in rodents and to competitively inhibit prostate 5α-reductase activity in vitro. Objective: The purpose of this study was to assess the effects of D-004 and LESP, administered as single or repeated doses, on the sexual activity in male rats. Methods: This controlled, experimental study was conducted at the Pharmacology Department, Centre of Natural Products, National Centre for Scientific Research, Havana City, Cuba. Adult male Wistar rats weighing 250 to 300 g were randomized into 5 groups: 2 groups treated orally with D-004 (400 and 800 mg/kg); 2 groups treated orally with LESP (400 and 800 mg/kg); and 1 control group orally administered a water vehicle. Sexual activity behavior (the number of mounts and intromissions, mount latency, and intromission latency) was assessed during 2 observation periods: 90 minutes after the initial dose and at the end of the 30-day treatment. Latency was defined as time elapsed between the first mount and intromission. Results: A total of 50 rats (mean [SD] age, 10 [3] weeks; mean [SD] weight, 295 [10] g) were included in the experiment. There were no significant difterences in the mean number of mounts, intromissions, mount latency, or intromission latency in the groups treated with single or repeated doses of D-004 or LESP

  10. Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study.

    PubMed

    Smith, Adrian P L; Marino, Michael; Roberts, Jeanette; Crowder, Janell M; Castle, Jason; Lowery, Lisa; Morton, Christine; Hibberd, Mark G; Evans, Paul M

    2017-03-01

    Purpose To measure the levels of gadolinium present in the rat brain 1 and 20 weeks after dosing with contrast agent and to determine if there are any histopathologic sequelae. Materials and Methods The study was approved by the GE Global Research Center Institutional Animal Care and Use Committee. Absolute gadolinium levels were quantified in the blood and brains of rats 1 week after dosing and 20 weeks after dosing with up to 20 repeat doses of gadodiamide (cumulative dose, 12 mmol per kilogram of body weight) by using inductively coupled plasma-mass spectrometry. Treatment groups (n = 6 rats per group) included low-dosage and high-dosage gadodiamide and osmolality-matched saline controls. Brain sections were submitted (blinded) for standard toxicology assessment per Registry of Industrial Toxicology Animal data guidelines. Analysis of variance and Mann-Whitney U tests with post hoc correction were used to assess differences in absolute gadolinium levels and percentage of injected dose, respectively. Results Dose-dependent low levels of gadolinium were detected in the brain, a mean ± standard deviation of 2.49 nmol per gram of brain tissue ± 0.30 or 0.00019% of the injected dose 1 week after dosing. This diminished by approximately 50% (to 1.38 nmol per gram of brain tissue ± 0.10 or 0.00011% of the injected dose) 20 weeks after dosing. As a percentage of injected dose, the levels of gadolinium measured were comparable between different doses, indicating that mechanisms of uptake and elimination were not saturated at the tested doses. There were no histopathologic findings associated with the levels of gadolinium measured. Conclusion Low levels of gadolinium are present in the brain after repeat dosing with gadodiamide, which is partially cleared over 20 weeks with no detectable neurotoxicity.

  11. Oral Toxicity Study and Skin Sensitization Test of a Cricket

    PubMed Central

    Ryu, Hyeon Yeol; Lee, Somin; Ahn, Kyu Sup; Kim, Hye Jin; Lee, Sang Sik; Ko, Hyuk Ju; Lee, Jin Kyu; Cho, Myung-Haing; Ahn, Mi Young; Kim, Eun Mi; Lim, Jeong Ho; Song, Kyung Seuk

    2016-01-01

    Crickets have been attracting considerable interest in the field of nutrition and toxicology due to the global exhaustion of food resulting from a growing population. The cricket is normally eaten in several countries after roasting, similar to the grasshopper; however, safety evaluation data on cricket powder is limited. Here, we performed general toxicity studies of cricket powder including a single, 2-week repeated dose range evaluation test, a 13-week repeated oral dose toxicity test in Sprague-Dawley rats, a single oral dose toxicity test in Beagle dogs, and a skin sensitization test in guinea pigs following the Organization for Economic Cooperation and Development test guidelines 406 and 408 in addition to Good Laboratory Practice. To investigate the NOAEL and target organs of cricket powder, Sprague-Dawley rats were allocated to 4 groups: vehicle control, 1,250 mg/kg, 2,500 mg/kg, 5,000 mg/kg dose test groups and cricket powder was administered over 13 weeks after single dose and dose range finding studies in rats based on the results of the single oral administration toxicity study in rats and Beagle dogs. The results of the study showed that the NOAEL of cricket powder was over 5,000 mg/kg for both sexes of rats without adverse effects in a 13-week repeated oral toxicity study and there was no skin hypersensitivity reaction. Therefore, our results reveal that crickets can be widely used as a new substitute food or nutrient resource. PMID:27123167

  12. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

    PubMed

    Andrade, E L; Bento, A F; Cavalli, J; Oliveira, S K; Schwanke, R C; Siqueira, J M; Freitas, C S; Marcon, R; Calixto, J B

    2016-12-12

    The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

  13. Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

    PubMed Central

    Andrade, E.L.; Bento, A.F.; Cavalli, J.; Oliveira, S.K.; Schwanke, R.C.; Siqueira, J.M.; Freitas, C.S.; Marcon, R.; Calixto, J.B.

    2016-01-01

    The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose. PMID:27982281

  14. Acute molecular markers of rodent hepatic carcinogenesis identified by transcription profiling.

    PubMed

    Kramer, Jeffrey A; Curtiss, Sandra W; Kolaja, Kyle L; Alden, Carl L; Blomme, Eric A G; Curtiss, William C; Davila, Julio C; Jackson, Carmen J; Bunch, Roderick T

    2004-04-01

    Currently, the only way to identify nongenotoxic hepatocarcinogens is through long-term repeat dose studies such as the 2 year rodent carcinogenicity assay. Such assays are both time consuming and expensive and require large amounts of active pharmaceutical or chemical ingredients. Thus, the results of the 2 year assay are not known until very late in the discovery and development process for new pharmaceutical entities. Although in many cases nongenotoxic carcinogenicity in rodents is considered to be irrelevant for humans, a positive finding in a 2 year carcinogenicity assay may increase the number of studies to demonstrate the lack of relevance to humans, delay final submission and subsequent registration of a product, and may result in a "black box" carcinogenicity warning on the label. To develop early identifiers of carcinogenicity, we applied transcription profiling using several prototype rodent genotoxic and nongenotoxic carcinogens, as well as two noncarcinogenic hepatotoxicants, in a 5 day repeat dose in vivo toxicology study. Fluorescent-labeled probes generated from liver mRNA prepared from male Sprague-Dawley rats treated with one of three dose levels of bemitradine, clofibrate, doxylamine, methapyrilene, phenobarbital, tamoxifen, 2-acetylaminofluorene, 4-acetylaminofluorene, or isoniazid were hybridized against rat cDNA microarrays. Correlation of the resulting data with an estimated carcinogenic potential of each compound and dose level identified several candidate molecular markers of rodent nongenotoxic carcinogenicity, including transforming growth factor-beta stimulated clone 22 and NAD(P)H cytochrome P450 oxidoreductase.

  15. Review of Ammonium Dinitramide Toxicity Studies

    DTIC Science & Technology

    2011-01-01

    standard acute toxicity tests with ADN ...........................................................3 Table 2. Results of repeated dose drinking water...traditional genotoxicity assays, including the Ames test , the mouse lymphoma cell mutagenesis test , and the in vivo mouse bone marrow micronuclei...enclosed cabinet. The test compound, as commonly available through SRI International (Menlo Park, CA), is known to be contaminated with 1 to 2 percent

  16. Metabolic changes in rats subjected to space flight for 18.5 days in the biosatellite Cosmos 936

    NASA Astrophysics Data System (ADS)

    Németh, Š.; Macho, L.; Palkovič, M.; Škottová, N.; Tigranyan, R. A.

    From an investigation of the activity of six glucocorticoid dependent liver enzymes, the existence of chronic, transient, stress-induced hypercorticosteronaemia during flight is probable. This hypercorticosteronaemia arises from weightlessness and induces gluconeogenesis. Weightlessness also caused substantial increases in liver glycogen level. The increased lipolytic activity and that of lipoprotein lipase in several groups of animals could be interpreted as enhancement of fat mobilization and utilization under the influence of stress. As this latter enhancement was also found in ground-based controls, it may have been due to the stress of handling rather than to space flight per se.

  17. Seasonal Variation of the Quasi 5 Day Planetary Wave: Causes and Consequences for Polar Mesospheric Cloud Variability in 2007

    DTIC Science & Technology

    2010-01-01

    t 1=2 C Y0 0ð Þ Xn i¼m Wr ai; bð Þ a1=2i : ðA6Þ [65] The constants depend on the mother wavelet used and the temporal resolution in the time series...may not be sufficiently large to generate responses in the analyzed humidity fields. [9] Merkel et al. [2009] and Eckermann et al. [2009] showed that...day wave in the polar mesosphere in greater temporal and spatial detail utilizing wavelet techniques. As satellite tempera- ture and water vapor

  18. 21 CFR 803.53 - If I am a manufacturer, in which circumstances must I submit a 5-day report?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES MEDICAL DEVICE REPORTING Manufacturer... the same nature that involve substantially similar devices for the time period specified in...

  19. 21 CFR 803.53 - If I am a manufacturer, in which circumstances must I submit a 5-day report?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES MEDICAL DEVICE REPORTING Manufacturer... the same nature that involve substantially similar devices for the time period specified in...

  20. [Direct proteomic profiling of human urine and blood serum in an experiment with 5-day dry immersion].

    PubMed

    2012-01-01

    Changes in proteome of urine and blood serum obtained from 14 healthy humans (age 21-29 yrs) medically certified for an experiment with dry immersion were analyzed. Urine and serum samples were pre-fractionated and enriched with magnetic particles MB-WCX and MB-HIC, respectively, on robot ClinProt (Bruker Daltonics) for direct mass-spectrometry profiling by MALDI-TOF. As a result, 143 protein peaks on the average were identified in urine samples. It was shown that a high variation coefficient in 23.7% of protein peaks, i.e. double technical, points to the most plastic fraction of the urine proteome. In blood serum, 175 peaks were identified in a sample on the average. Comparison of baseline and immersion mass-spectra of the blood proteome revealed significant differences. Increased peak areas of several protein fragments--C3 and C4 fragments of complement system, high-molecular kininogen and fibrinogen--can be ascribed to human body adaptation to the experimental conditions.

  1. Changes in Nutrient Intakes of Conditioned Men during a 5-Day Period of Increased Physical Activity and Other Stresses

    DTIC Science & Technology

    1988-06-01

    SUBJECT TERMS (Continue on reverse if necessary and identify by block number) FIELD GROUP SUB-GROUP nutrition minerals energy balanQe vitamins 19...Introduction and urinary constituents of 16 Navy servicemen were obtained before and during a period of 113 It is an axiom that proper nutrition will...deprivation. Psychological stresses included verbal confrontations, perform- Key words: Nutrition >- Energy balance -- Vita- ance anxiety, and activities with

  2. Assessment of knowledge of participants on basic molecular biology techniques after 5-day intensive molecular biology training workshops in Nigeria.

    PubMed

    Yisau, J I; Adagbada, A O; Bamidele, T; Fowora, M; Brai, B I C; Adebesin, O; Bamidele, M; Fesobi, T; Nwaokorie, F O; Ajayi, A; Smith, S I

    2017-02-01

    The deployment of molecular biology techniques for diagnosis and research in Nigeria is faced with a number of challenges, including the cost of equipment and reagents coupled with the dearth of personnel skilled in the procedures and handling of equipment. Short molecular biology training workshops were conducted at the Nigerian Institute of Medical Research (NIMR), to improve the knowledge and skills of laboratory personnel and academics in health, research, and educational facilities. Five-day molecular biology workshops were conducted annually between 2011 and 2014, with participants drawn from health, research facilities, and the academia. The courses consisted of theoretical and practical sessions. The impact of the workshops on knowledge and skill acquisition was evaluated by pre- and post-tests which consisted of 25 multiple choice and other questions. Sixty-five participants took part in the workshops. The mean knowledge of molecular biology as evaluated by the pre- and post-test assessments were 8.4 (95% CI 7.6-9.1) and 13.0 (95 CI 11.9-14.1), respectively. The mean post-test score was significantly greater than the mean pre-test score (p < 0.0001). The five-day molecular biology workshop significantly increased the knowledge and skills of participants in molecular biology techniques. © 2017 by The International Union of Biochemistry and Molecular Biology, 2017.

  3. KELT-12b: A P ∼ 5 day, Highly Inflated Hot Jupiter Transiting a Mildly Evolved Hot Star

    NASA Astrophysics Data System (ADS)

    Stevens, Daniel J.; Collins, Karen A.; Gaudi, B. Scott; Beatty, Thomas G.; Siverd, Robert J.; Bieryla, Allyson; Fulton, Benjamin J.; Crepp, Justin R.; Gonzales, Erica J.; Coker, Carl T.; Penev, Kaloyan; Stassun, Keivan G.; Jensen, Eric L. N.; Howard, Andrew W.; Latham, David W.; Rodriguez, Joseph E.; Zambelli, Roberto; Bozza, Valerio; Reed, Phillip A.; Gregorio, Joao; Buchhave, Lars A.; Penny, Matthew T.; Pepper, Joshua; Berlind, Perry; Calchi Novati, Sebastiano; Calkins, Michael L.; D’Ago, Giuseppe; Eastman, Jason D.; Bayliss, D.; Colón, Knicole D.; Curtis, Ivan A.; DePoy, D. L.; Esquerdo, Gilbert A.; Gould, Andrew; Joner, Michael D.; Kielkopf, John F.; Labadie-Bartz, Jonathan; Lund, Michael B.; Manner, Mark; Marshall, Jennifer L.; McLeod, Kim K.; Oberst, Thomas E.; Pogge, Richard W.; Scarpetta, Gaetano; Stephens, Denise C.; Stockdale, Christopher; Tan, T. G.; Trueblood, Mark; Trueblood, Patricia

    2017-04-01

    We announce the discovery of KELT-12b, a highly inflated Jupiter-mass planet transiting the mildly evolved, V = 10.64 host star TYC 2619-1057-1. We followed up the initial transit signal in the KELT-North survey data with precise ground-based photometry, high-resolution spectroscopy, precise radial velocity measurements, and high-resolution adaptive optics imaging. Our preferred best-fit model indicates that the host star has {T}{eff} = 6279 ± 51 K, {log}{g}\\star = 3.89 ± 0.05, [Fe/H] = {0.19}-0.09+0.08, {M}* = {1.59}-0.09+0.07 {M}ȯ , and {R}* = 2.37 ± 0.17 {R}ȯ . The planetary companion has {M}{{P}} = 0.95 ± 0.14 {M}{{J}}, {R}{{P}} = {1.78}-0.16+0.17 {R}{{J}}, {log}{g}{{P}} = {2.87}-0.10+0.09, and density {ρ }{{P}} = {0.21}-0.05+0.07 g cm‑3, making it one of the most inflated giant planets known. Furthermore, for future follow-up, we report a high-precision time of inferior conjunction in {{BJD}}{TDB} of 2,457,083.660459 ± 0.000894 and period of P=5.0316216+/- 0.000032 days. Despite the relatively large separation of ∼0.07 au implied by its ∼5.03-day orbital period, KELT-12b receives significant flux of {2.38}-0.29+0.32× {10}9 erg s‑1 cm‑2 from its host. We compare the radii and insolations of transiting gas giant planets around hot ({T}{eff}≥slant 6250 K) and cool stars, noting that the observed paucity of known transiting giants around hot stars with low insolation is likely due to selection effects. We underscore the significance of long-term ground-based monitoring of hot stars and space-based targeting of hot stars with the Transiting Exoplanet Survey Satellite to search for inflated gas giants in longer-period orbits.

  4. Comparison of Aerobic Power and Dynamic Lift Capacity with Performance during a 5-Day Sustained Combat Scenario

    DTIC Science & Technology

    1984-12-31

    evaluator team. Evaluators will bring AREA I books and tapes back with them to the TOC, in addition to all special equipment (i.e., radio). 3. Time...new evaluator team. Evaluators will bring book and tapes back with them to the TOC, in addition to all special equipment (i.e., radio). All...physiological tapes collected befbre changing over with new evaluator team. Evaluators willSbring Area III book and tapessback with them to TOC in addition to

  5. Comparative study of toxicity of 4-nitrophenol and 2,4-dinitrophenol in newborn and young rats.

    PubMed

    Koizumi, M; Yamamoto, Y; Ito, Y; Takano, M; Enami, T; Kamata, E; Hasegawa, R

    2001-12-01

    The toxicities of 4-nitrophenol and 2,4-dinitrophenol in newborn and young rats was examined and the susceptibility of newborn rats was analyzed in terms of presumed unequivocally toxic and no observed adverse effect levels (NOAELs). In the 18-day repeated dose newborn rat study, 4-nitrophenol was orally given from Day 4 to Day 21 after birth but did not induce any toxicity up to 160 mg/kg in the main study, although it induced death in one of six males at 160 mg/kg, and three of six males and one of six females at 230 mg/kg in a prior dose-finding study. In the 28-day repeated dose oral toxicity study starting at 6 weeks of age, 4-nitrophenol caused the death of most males and females at 1,000 mg/kg but was not toxic at 400 mg/kg except for male rat-specific renal toxicity. As unequivocally toxic levels were considered to be 230 mg/kg/day in newborn rats and 600 to 800 mg/kg/day in young rats, and NOAELs were 110 mg/kg/day in newborn rats and 400 mg/kg/day in young rats, the susceptibility of the newborn to 4-nitrophenol appears to be 2.5 to 4 times higher than that of young animals. In the newborn rat study of 2,4-dinitrophenol, animals died at 30 mg/kg in the dose-finding study and significant lowering of body and organ weights was observed at 20 mg/kg in the main study. In the 28-day young rat study, clear toxic signs followed by death occurred at 80 mg/kg but there was no definitive toxicity at 20 mg/kg. As unequivocally toxic levels and NOAELs were considered to be 30 and 10 mg/kg/day in newborn rats and 80 and 20 mg/kg/day in young rats, respectively, the toxicity of 2,4-dinitrophenol in newborns again seems to be 2 to 3 times stronger than in young rats. Abnormalities of external development and reflex ontogeny in the newborn were not observed with either chemical. Based on these results, it can be concluded that the toxic response in newborn rats is at most 4 times higher than that in young rats, at least in the cases of 4-nitrophenol and 2,4-dinitrophenol.

  6. Non-Clinical Safety Studies of IMT504, a Unique Non-CpG Oligonucleotide

    PubMed Central

    Franco, Raúl; Rodriguez, Juan M.; Elías, Fernanda; Hernando-Insúa, Andrés; Fló, Juan; López, Ricardo; Nagle, Carlos; Lago, Néstor; Zorzopulos, Jorge; Horn, David L.

    2014-01-01

    IMT504 is a non-CpG 24-mer oligodeoxynucleotide (ODN) with immunomodulatory as well as tissue repair activity. IMT504 has been previously proven to be effective in animal models of vaccine potency, chronic lymphocytic leukemia, tissue regeneration, and sepsis. Here, we assessed the safety, including pharmacokinetics and toxicity studies in rats and monkeys, of IMT504 in a single- or repeated-dose administration by the subcutaneous (SC) or intravenous (IV) routes. In rats, the maximum tolerated dose was determined to be 50 mg/kg when administered SC. Adverse effects at 50 mg/kg were mild and reversible liver injury, revealed as lobular inflammation, focal necrosis, and small changes in the transaminase profile. Dose-dependent splenomegaly and lymphoid hyperplasia, most probably associated with immune stimulation, were commonly observed. Rats and monkeys were also IV injected with a single dose of 10 or 3.5 mg/kg, and no adverse effects were observed. Rats injected IV with 10 mg/kg showed a transient increase in spleen weight, together with a slight increase in the marginal zone of the white pulp and in leukocyte count 2 days post-administration. In monkeys, this dosage caused slight changes in total serum complement and leukocyte count on day 14. No adverse effects were observed at 3.5 mg/kg IV in rats or monkeys. Therefore, this dose was defined as the “no observed adverse effect level” for this route. Furthermore, repeated-dose toxicity studies were performed in these species using 3.5 or 0.35 mg/kg/day IV for 6 weeks. A transient increase in the spleen and liver weight was observed at 3.5 mg/kg/day only in female rats. No changes in clotting time and activation of the alternative complement pathway were observed. The toxicity profile of IMT504 herein reported suggests a dose range in which IMT504 can be used safely in clinical trials. PMID:24720569

  7. Integrating experimental (in vitro and in vivo) neurotoxicity studies of low-dose thimerosal relevant to vaccines.

    PubMed

    Dórea, José G

    2011-06-01

    There is a need to interpret neurotoxic studies to help deal with uncertainties surrounding pregnant mothers, newborns and young children who must receive repeated doses of Thimerosal-containing vaccines (TCVs). This review integrates information derived from emerging experimental studies (in vitro and in vivo) of low-dose Thimerosal (sodium ethyl mercury thiosalicylate). Major databases (PubMed and Web-of-science) were searched for in vitro and in vivo experimental studies that addressed the effects of low-dose Thimerosal (or ethylmercury) on neural tissues and animal behaviour. Information extracted from studies indicates that: (a) activity of low doses of Thimerosal against isolated human and animal brain cells was found in all studies and is consistent with Hg neurotoxicity; (b) the neurotoxic effect of ethylmercury has not been studied with co-occurring adjuvant-Al in TCVs; (c) animal studies have shown that exposure to Thimerosal-Hg can lead to accumulation of inorganic Hg in brain, and that (d) doses relevant to TCV exposure possess the potential to affect human neuro-development. Thimerosal at concentrations relevant for infants' exposure (in vaccines) is toxic to cultured human-brain cells and to laboratory animals. The persisting use of TCV (in developing countries) is counterintuitive to global efforts to lower Hg exposure and to ban Hg in medical products; its continued use in TCV requires evaluation of a sufficiently nontoxic level of ethylmercury compatible with repeated exposure (co-occurring with adjuvant-Al) during early life.

  8. Toxicity study of food-grade carboxymethyl cellulose synthesized from maize husk in Swiss albino mice.

    PubMed

    Mondal, Md Ibrahim H; Yeasmin, Mst Sarmina

    2016-11-01

    Food-grade carboxymethyl cellulose was prepared from maize husk agro-waste and was evaluated sub-chronic oral toxicity in Swiss albino mice. 40 male mice were divided into 4 groups and fed diets with 0 (control) - 10% CMC for a period of 3 months. Daily oral doses were 5 - 20mg/g body weight to the mice/day. Animal care and handling were conformed according to internationally accepted standard guidelines. Haematological and biochemical parameters were monitored during this period. At the end of the study, tissues and organs were studied for histopathological changes. Repeat-dose oral toxicity study was carried out according to OECD guideline 408. The result did not show any treatment related abnormalities in terms of haematological and biochemical parameters. However, water intake, urine production and urinary sodium excretion increased with increasing doses of CMC. The weekly body weight showed no significant differences between control and mice treated with different doses of CMC. In mice of the treated groups, no abnormalities in the histopathology of liver, heart, lung and kidney were detected. This indicated the prepared CMC has no toxic effect at different doses on cellular structure, and support the safety use of CMC as food additives and an excipient for pharmaceuticals.

  9. Acute and Subchronic Toxicity Study of Euphorbia hirta L. Methanol Extract in Rats

    PubMed Central

    Yuet Ping, Kwan; Darah, Ibrahim; Chen, Yeng; Sreeramanan, Subramaniam

    2013-01-01

    Despite Euphorbia hirta L. ethnomedicinal benefits, very few studies have described the potential toxicity. The aim of the present study was to evaluate the in vivo toxicity of methanolic extracts of E. hirta. The acute and subchronic oral toxicity of E. hirta was evaluated in Sprague Dawley rats. The extract at a single dose of 5000 mg/kg did not produce treatment related signs of toxicity or mortality in any of the animals tested during the 14-day observation period. Therefore, the LD 50 of this plant was estimated to be more than 5000 mg/kg. In the repeated dose 90-day oral toxicity study, the administration of 50 mg/kg, 250 mg/kg, and 1000 mg/kg/day of E. hirta extract per body weight revealed no significant difference (P > 0.05) in food and water consumptions, body weight change, haematological and biochemical parameters, relative organ weights, and gross findings compared to the control group. Macropathology and histopathology examinations of all organs including the liver did not reveal morphological alteration. Analyses of these results with the information of signs, behaviour, and health monitoring could lead to the conclusion that the long-term oral administration of E. hirta extract for 90 days does not cause sub-chronic toxicity. PMID:24386634

  10. Safety Evaluation of Zingiber cassumunar Roxb. Rhizome Extract: Acute and Chronic Toxicity Studies in Rats

    PubMed Central

    Koontongkaew, Sittichai; Poachanukoon, Orapan; Sireeratawong, Seewaboon; Dechatiwongse Na Ayudhya, Thaweephol; Khonsung, Parirat; Jaijoy, Kanjana; Soawakontha, Ruedee; Chanchai, Monraudee

    2014-01-01

    Zingiber cassumunar Roxb. has been used for traditional medicine, but few studies have described its potential toxicity. In this study, the acute and chronic oral toxicity of Z. cassumunar extract granules were evaluated in Sprague-Dawley rats. The extract at a single dose of 5000 mg/kg body weight did not produce treatment related signs of toxicity or mortality in any of the animals tested during the 14-day observation period. However, a decrease in body weights was observed in treated males (P < 0.05). The weights of lung and kidney of treated females were increased (P < 0.05). Treated males were increased in spleen and epididymis weights (P < 0.05). In repeated dose 270-day oral toxicity study, the administration of the extracts at concentrations of 0.3, 3, 30, 11.25, 112.5, and 1,125 mg/kg body weight/day revealed no-treatment toxicity. Although certain endpoints among those monitored (i.e., organ weight, hematological parameters, and clinical chemistry) exhibited statistically significant effects, none was adverse. Gross and histological observations revealed no toxicity. Our findings suggest that the Z. cassumunar extract granules are well tolerated for both single and chronic administration. The oral no-observed-adverse-effect level (NOAEL) for the extract was 1,125 mg/kg body weight/day for males and females. PMID:27379341

  11. Safety Evaluation of Zingiber cassumunar Roxb. Rhizome Extract: Acute and Chronic Toxicity Studies in Rats.

    PubMed

    Koontongkaew, Sittichai; Poachanukoon, Orapan; Sireeratawong, Seewaboon; Dechatiwongse Na Ayudhya, Thaweephol; Khonsung, Parirat; Jaijoy, Kanjana; Soawakontha, Ruedee; Chanchai, Monraudee

    2014-01-01

    Zingiber cassumunar Roxb. has been used for traditional medicine, but few studies have described its potential toxicity. In this study, the acute and chronic oral toxicity of Z. cassumunar extract granules were evaluated in Sprague-Dawley rats. The extract at a single dose of 5000 mg/kg body weight did not produce treatment related signs of toxicity or mortality in any of the animals tested during the 14-day observation period. However, a decrease in body weights was observed in treated males (P < 0.05). The weights of lung and kidney of treated females were increased (P < 0.05). Treated males were increased in spleen and epididymis weights (P < 0.05). In repeated dose 270-day oral toxicity study, the administration of the extracts at concentrations of 0.3, 3, 30, 11.25, 112.5, and 1,125 mg/kg body weight/day revealed no-treatment toxicity. Although certain endpoints among those monitored (i.e., organ weight, hematological parameters, and clinical chemistry) exhibited statistically significant effects, none was adverse. Gross and histological observations revealed no toxicity. Our findings suggest that the Z. cassumunar extract granules are well tolerated for both single and chronic administration. The oral no-observed-adverse-effect level (NOAEL) for the extract was 1,125 mg/kg body weight/day for males and females.

  12. Acute and environmental toxicity studies with hexazinone.

    PubMed

    Kennedy, G L

    1984-08-01

    The acute toxicity of hexazinone, a herbicide intended for general noncropland areas and selected crop uses (alfalfa and sugarcane), has been evaluated to establish proper handling guidelines and to measure its potential impact on the environment. The material is slightly to moderately toxic when given as a single oral dose; its LD50 in male rats is 1690 mg/kg, in male guinea pigs 860 mg/kg, and in male dogs greater than 3400 mg/kg although in the dog emesis prevented accurate quantitation. When the material is administered intraperitoneally, the LD50 in rats is 530 mg/kg. Repeated doses (five oral doses per week for 2 weeks) of 300 mg/kg to rats produced slight weight loss in one of two replicate experiments. In both studies, no gross or histologic alterations were apparent. Hexazinone is a moderate to severe eye irritant in the rabbit and produced only mild erythema in rabbit skin at 5278 mg/kg, a dose which did not produce lethality or other clinical signs. Subchronic dermal exposures (10 consecutive doses) to rabbits produced increases in serum alkaline phosphatase and glutamic-pyruvic transaminase at the highest levels tested (680 and 770 mg/kg in two separate experiments) with no effects seen at 150 mg/kg. There were no alterations in livers from treated rabbits examined by light microscopy. No dermal sensitization was produced when concentrations of up to 50% were tested in guinea pigs. One-hour inhalation exposure of up to 7.48 mg/liter did not produce mortality in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. [Gymnema sylvestre leaf extract: a 52-week dietary toxicity study in Wistar rats].

    PubMed

    Ogawa, Yukio; Sekita, Kiyoshi; Umemura, Takashi; Saito, Minoru; Ono, Atsushi; Kawasaki, Yasushi; Uchida, Osayuki; Matsushima, Yuko; Inoue, Tohru; Kanno, Jun

    2004-02-01

    A 52-week study of oral-repeated-dose toxicity for the extraction powder of Gymnema sylvestre (GS), Indian-native genus, Metaplexis japonica, was conducted in both genders of Wistar rats. The rats were administered a graded dose of GS at 0.01, 0.10 and 1.00% of basal powder diet, along with a group fed solely with the basal powder diet without GS, for 52 weeks. General conditions were recorded daily. Body weights and food consumptions were recorded weekly up to 12 weeks, and thereafter at longer intervals. At 26 weeks, for an intermediate examination, and 52 weeks, for the final examination, animals were subjected to hematology, serum chemistry, and pathological examination. None of the animals died in the period up to 52 weeks. No exposure-related changes in body-weight, in the food consumption, in the hematological examinations, or in the serum biochemical examinations were recognized. No histopathological alterations were seen. Thus, it was concluded that there was no toxic effect in rats treated with GS at up to 1.00% in the diet for 52 weeks. The no-observable-effect level from this study is 1.00% GS, i.e., 504 mg/kg/day for male and 563 mg/kg/day for female as mean daily intake, for 52 weeks.

  14. A subchronic 90-day oral toxicity study of Origanum vulgare essential oil in rats.

    PubMed

    Llana-Ruiz-Cabello, M; Maisanaba, S; Puerto, M; Pichardo, S; Jos, A; Moyano, R; Cameán, A M

    2017-03-01

    Oregano essential oil (Origanum vulgare L. virens) (OEO) is being used in the food industry due to its useful properties to develop new active packaging systems. In this concern, the safety assessment of this natural extract is of great interest before being commercialized. The European Food Safety Authority requests different in vivo assays to ensure the safety of food contact materials. One of these studies is a 90 days repeated-dose oral assay in rodents. In the present work, 40 male and 40 female Wistar rats were orally exposed to 50, 100 and 200 mg/kg body weight (b.w.) OEO during 90 days following the OECD guideline 408. Data revealed no mortality and no treatment-related adverse effects of the OEO in food/water consumption, body weight, haematology, biochemistry, necropsy, organ weight and histopathology. These findings suggest that the oral no-observed-adverse-effect level (NOAEL) of this OEO is 200 mg/kg b.w. in Wistar rats, the highest dose tested. In conclusion, the use of this OEO in food packaging appears to be safe based on the lack of toxicity during the subchronic study at doses 330-fold higher than those expected to be in contact consumers in the worst scenario of exposure.

  15. Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water.

    PubMed

    Cullen, John M; Ward, Jerrold M; Thompson, Chad M

    2016-02-01

    Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response.

  16. Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water

    PubMed Central

    Cullen, John M.; Ward, Jerrold M.

    2015-01-01

    Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response. PMID:26538584

  17. Toxicological studies of aqueous extract of Acacia nilotica root

    PubMed Central

    Adesokan, Abdulfatai Ayoade; Salawu, Oluwakanyinsola Adeola; Akanji, Musbau Adewunmi

    2015-01-01

    Acacia nilotica is a widely used plant in traditional medical practice in Northern Nigeria and many African countries. The aim of this study was to determine the toxicological effects of a single dose (acute) and of repeated doses (sub-acute) administration of aqueous extract of A. nilotica root in rodents, following our earlier study on antiplasmodial activity. In the acute toxicity test, three groups of Swiss albino mice were orally administered aqueous extract of A. nilotica (50, 300 and 2000 mg/kg body weight) and signs of toxicity were observed daily for 14 days. In the sub-acute toxicity study, four groups of 12 rats (6 male and 6 female) were used. Group 1 received 10 ml/kg b.w distilled water (control), while groups 2, 3 and 4 received 125, 250 and 500 mg/kg b.w of the extract, respectively, for 28 consecutive days by oral gavage. Signs of toxicity/mortality, food and water intake and body weight changes were observed. Biochemical parameters were analysed in both plasma and liver homogenate. In the acute and sub-acute toxicity studies, the extract did not cause mortality. A significant reduction in the activity of lactate dehydrogenase was observed at 250 and 500 mg/kg b.w, while alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities were significantly higher than control values at 500 mg/kg b.w. The aqueous extract of A. nilotica was found to be safe in single dose administration in mice but repeated administration of doses higher than 250 mg/kg b.w of the extract for 28 days in rats may cause hepatotoxicity. PMID:27486360

  18. The acute effects of daily nicotine intake on heart rate--a toxicokinetic and toxicodynamic modelling study.

    PubMed

    Gajewska, M; Worth, A; Urani, C; Briesen, H; Schramm, K-W

    2014-10-01

    Joint physiologically-based toxicokinetic and toxicodynamic (PBTK/TD) modelling was applied to simulate concentration-time profiles of nicotine, a well-known stimulant, in the human body following single and repeated dosing. Both kinetic and dynamic models were first calibrated by using in vivo literature data for the Caucasian population. The models were then used to estimate the blood and liver concentrations of nicotine in terms of the Area Under Curve (AUC) and the peak concentration (Cmax) for selected exposure scenarios based on inhalation (cigarette smoking), oral intake (nicotine lozenges) and dermal absorption (nicotine patches). The model simulations indicated that whereas frequent cigarette smoking gives rise to high AUC and Cmax in blood, the use of nicotine-rich dermal patches leads to high AUC and Cmax in the liver. Venous blood concentrations were used to estimate one of the most common acute effects, mean heart rate, both at rest and during exercise. These estimations showed that cigarette smoking causes a high peak heart rate, whereas dermal absorption causes a high mean heart rate over 48h. This study illustrates the potential of using PBTK/TD modelling in the safety assessment of nicotine-containing products.

  19. Toxicology studies with recombinant staphylokinase and with SY 161-P5, a polyethylene glycol-derivatized cysteine-substitution mutant.

    PubMed

    Moons, L; Vanlinthout, I; Roelants, I; Moreadith, R; Collen, D; Rapold, H J

    2001-01-01

    SY 161-P5, a polyethylene glycol derivatized (PEGylated) mutant of the recombinant Staphylokinase (rSak) variant SakSTAR, exhibiting reduced antigenicity is in clinical development for treatment of acute myocardial infarction as a single bolus injection. A series of safety studies were performed in vivo as a routine toxicology program with SY 161-P5 (PEG-rSakSTAR) and with the recombinant Staphylokinase variant Sak42D (rSak42D). For both compounds, intravenous single bolus injections of up to 100-fold therapeutic equivalent, as well as repeated injections during 7 to 28 days revealed no significant pathological findings in mice, rats or hamsters. However, New Zealand white rabbits developed clinically silent, multifocal myocarditis following single or repeat doses of SY 161-P5 or of Sak42D. These findings were dose-independent and reversible. A similar species-specific cardiotoxic effect has previously been described for other proteolytic proteins, including the approved drugs Streptokinase and Acetylated Plasminogen Streptokinase Complex (APSAC). The large experience with these drugs, as well as the clinical data accumulated both with PEGylated and non-PEGylated rSak variants to date, do not indicate cardiotoxic hazards associated with the use of these drugs in humans.

  20. Cosmos: 1989 immunology studies

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald

    1991-01-01

    The effects of flight on Cosmos mission 2044 on leukocyte subset distribution and the sensitivity of bone marrow cells to colony stimulating factor-GM were determined. A parallel study with antiorthostatic suspension was also carried out. The study involved repetition and expansion of studies performed on Cosmos 1887. Spleen and bone marrow cells were obtained from flown, vivarium control, synchronous control, and suspended rats. The cells were stained with a series of monoclonal antibodies directed against rat leukocyte cell surface antigens. Control cells were stained with a monoclonal antibody directed against an irrelevant species or were unstained. Cells were then analyzed for fluorescence using a FACSCAN flow cytometer. Bone marrow cells were placed in culture with GM-CSF in McCoy's 5a medium and incubated for 5 days. Cultures were then evaluated for the number of colonies of 50 cells or greater.

  1. Depressed patients’ preferences for type of psychotherapy: a preliminary study

    PubMed Central

    Yrondi, Antoine; Rieu, Julie; Massip, Claire; Bongard, Vanina; Schmitt, Laurent

    2015-01-01

    Background The treatment recommendations for depressed patients by the American Psychiatric Association encourage a focus on the patient’s preferences. The focus of this study was the preference of depressed inpatients for the type of psychotherapy. Methods Twenty-nine subjects of both sexes who were hospitalized with a major depressive episode were interviewed at 5-day intervals with the same questions after the depressive episode resolved, as indicated by a score less than 7 on the Hamilton Depression Rating Scale (HDRS). The selection of items was performed by expert consensus. Results The supportive psychotherapy scores were the highest, followed by psychodynamic psychotherapy and cognitive behavioral therapy. The two sessions conducted at 5-day intervals showed no significant difference, which reflected the stability of choices and preferences of patients. Conclusion In this study, the patients preferred supportive psychotherapy as first-line therapy compared to psychodynamic psychotherapy and cognitive behavioral therapy. PMID:26491265

  2. Pesticide Exposure and Neurodevelopmental Outcomes: Review of the Epidemiologic and Animal Studies

    PubMed Central

    Burns, Carol J.; McIntosh, Laura J.; Mink, Pamela J.; Jurek, Anne M.; Li, Abby A.

    2013-01-01

    Assessment of whether pesticide exposure is associated with neurodevelopmental outcomes in children can best be addressed with a systematic review of both the human and animal peer-reviewed literature. This review analyzed epidemiologic studies testing the hypothesis that exposure to pesticides during pregnancy and/or early childhood is associated with neurodevelopmental outcomes in children. Studies that directly queried pesticide exposure (e.g., via questionnaire or interview) or measured pesticide or metabolite levels in biological specimens from study participants (e.g., blood, urine, etc.) or their immediate environment (e.g., personal air monitoring, home dust samples, etc.) were eligible for inclusion. Consistency, strength of association, and dose response were key elements of the framework utilized for evaluating epidemiologic studies. As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children. A few associations were unique for a health outcome and specific pesticide, and alternative hypotheses could not be ruled out. Our survey of the in vivo peer-reviewed published mammalian literature focused on effects of the specific active ingredient of pesticides on functional neurodevelopmental endpoints (i.e., behavior, neuropharmacology and neuropathology). In most cases, effects were noted at dose levels within the same order of magnitude or higher compared to the point of departure used for chronic risk assessments in the United States. Thus, although the published animal studies may have characterized potential neurodevelopmental outcomes using endpoints not required by guideline studies, the effects were generally observed at or above effect levels measured in repeated-dose toxicology studies submitted to the U.S. Environmental Protection Agency (EPA). Suggestions for improved exposure assessment in epidemiology studies and more effective

  3. Pesticide exposure and neurodevelopmental outcomes: review of the epidemiologic and animal studies.

    PubMed

    Burns, Carol J; McIntosh, Laura J; Mink, Pamela J; Jurek, Anne M; Li, Abby A

    2013-01-01

    Assessment of whether pesticide exposure is associated with neurodevelopmental outcomes in children can best be addressed with a systematic review of both the human and animal peer-reviewed literature. This review analyzed epidemiologic studies testing the hypothesis that exposure to pesticides during pregnancy and/or early childhood is associated with neurodevelopmental outcomes in children. Studies that directly queried pesticide exposure (e.g., via questionnaire or interview) or measured pesticide or metabolite levels in biological specimens from study participants (e.g., blood, urine, etc.) or their immediate environment (e.g., personal air monitoring, home dust samples, etc.) were eligible for inclusion. Consistency, strength of association, and dose response were key elements of the framework utilized for evaluating epidemiologic studies. As a whole, the epidemiologic studies did not strongly implicate any particular pesticide as being causally related to adverse neurodevelopmental outcomes in infants and children. A few associations were unique for a health outcome and specific pesticide, and alternative hypotheses could not be ruled out. Our survey of the in vivo peer-reviewed published mammalian literature focused on effects of the specific active ingredient of pesticides on functional neurodevelopmental endpoints (i.e., behavior, neuropharmacology and neuropathology). In most cases, effects were noted at dose levels within the same order of magnitude or higher compared to the point of departure used for chronic risk assessments in the United States. Thus, although the published animal studies may have characterized potential neurodevelopmental outcomes using endpoints not required by guideline studies, the effects were generally observed at or above effect levels measured in repeated-dose toxicology studies submitted to the U.S. Environmental Protection Agency (EPA). Suggestions for improved exposure assessment in epidemiology studies and more effective

  4. Evaluating the male and female reproductive toxicity of high-boiling petroleum substances.

    PubMed

    Murray, F Jay; Gray, Thomas M; Roberts, Linda G; Roth, Randy N; Nicolich, Mark J; Simpson, Barry J

    2013-11-01

    To meet the EPA HPV Chemical Challenge Program requirement for reproductive toxicity data on sponsored high-boiling petroleum substances (HBPS), an analysis was conducted using the results of 39 repeat-dose and 59 developmental rat dermal toxicity studies on HBPS samples spanning the boiling range of the sponsored substances, and the results of three one-generation reproductive toxicity studies on two samples spanning the concentration range of polycyclic aromatic compounds of sponsored substances. The analysis found little evidence of male or female reproductive tract toxicity based on histopathology, reproductive organ weight, and sperm parameters, and no evidence of effects on fertility, while significant developmental toxicity and/or systemic repeat-dose toxicity were frequently observed. Among 14 samples of HBPS tested in both repeat-dose toxicity and developmental toxicity studies, there were no studies in which an adverse reproductive tract finding occurred at a dose lower than that producing developmental toxicity or other adverse effects in repeat-dose toxicity studies. The current analysis supports the hypothesis that effects in developmental and/or repeat-dose toxicity studies of HBPS occur at doses lower than those that might affect fertility in rat one-generation reproductive studies. When adequate developmental and repeat-dose toxicity studies are available, a reproductive toxicity study of HBPS appears unnecessary.

  5. The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene.

    PubMed

    Yoo, Hong Sik; Cichocki, Joseph A; Kim, Sungkyoon; Venkatratnam, Abhishek; Iwata, Yasuhiro; Kosyk, Oksana; Bodnar, Wanda; Sweet, Stephen; Knap, Anthony; Wade, Terry; Campbell, Jerry; Clewell, Harvey J; Melnyk, Stepan B; Chiu, Weihsueh A; Rusyn, Ivan

    2015-10-01

    Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor

  6. NT-07PHASE 1-2 DOSE-ESCALATION STUDY OF VB-111, AN ANTI-ANGIOGENIC GENE THERAPY, AS MONOTHERAPY AND IN COMBINATION WITH BEVACIZUMAB, IN PATIENTS WITH RECURRENT GLIOBLASTOMA

    PubMed Central

    Brenner, Andrew; Cohen, Yael; Vredenburgh, James; Peters, Katherine; Blumenthal, Deborah; Bokstein, Felix; Breitbart, Eyal; Bangio, Livnat; Sher, Naamit; Harats, Dror; Wen, Patrick

    2014-01-01

    BACKGROUND: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. Safety and efficacy of VB-111 alone and in combination with bevacizumab (BEV) were evaluated for patients with recurrent Glioblastoma (rGBM) in this phase 1-2 dose-escalation study. METHODS: VB-111 was administered as a single intravenous infusion at escalating doses from 1x1012 to 1x1013 viral particles (VPs), followed by repeat doses of 3x1012 or 1x1013 every 2 months. The protocol was amended to add-on BEV 10mg/Kg every 2 weeks upon further progression. Assessments included safety, pharmacokinetics, tumor response (RANO criteria) and overall survival (OS). RESULTS: Forty-six patients at 4 recruiting medical centers in the US and Israel received up to 13 repeat doses of VB-111. Of these 30 received the high dose (1x1013). There were 22 related adverse events, 19 CTCAE grade 1-2. The median OS was 360 [range: 70-574] and 266 days [range: 28-664] for patients receiving at least one high dose vs. subjects who received lower doses, respectively (p NS). Progression free survival was 63 vs. 55 days for patients who received high vs. lower doses, respectively (p = 0.01). Median follow-up was 232 days. Six patients had a partial response and/or prolonged disease stability (≥180 days). Tumor growth rates showed a statistically significant dose response. Eleven patients received combination therapy of VB-111 with BEV after progression on VB-111 alone. Median time to second progression was 93 days. VB-111 was safe and well tolerated both as monotherapy and combined therapy. CONCLUSIONS: VB-111 was safe and well tolerated as monotherapy and in combination with BEV in patients with recurrent glioblastoma. Encouraging tumor growth attenuation and responses were seen. Overall survival was about 3 months longer

  7. An Exploratory Dose-Escalating Study Investigating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous Atacicept in Patients with Systemic Lupus Erythematosus

    PubMed Central

    Pena-Rossi, C; Nasonov, E; Stanislav, M; Yakusevich, V; Ershova, O; Lomareva, N; Saunders, H; Hill, J; Nestorov, I

    2009-01-01

    Atacicept, a recombinant fusion protein containing the extracellular, ligand-binding portion of the transmembrane activator and calcium modulator and cyclophilin-ligand interactor receptor, and the Fc portion of human immunoglobulin (Ig) G, is designed to block the activity of B-lymphocyte stimulator and a proliferation-inducing ligand, and may have utility as a treatment for B-cellmediated diseases, such as systemic lupus erythematosus (SLE). This Phase Ib study investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of intravenous (i.v.) atacicept in patients with mild-to-moderate SLE. Patients (n = 24) were randomised (5:1) to receive atacicept (single dose: 3, 9 or 18 mg/kg; or multiple dose: 2 × 9 mg/kg) or matching placebo. Patients were followed for 6 weeks after dosing (9 weeks in the 2 × 9 mg/kg cohort). Local tolerability of atacicept was comparable with that of placebo, with only mild injection-site reactions reported with atacicept. Atacicept i.v. was generally well tolerated, both systemically and locally, in patients with mild-to-moderate SLE. Atacicept displayed non-linear PK, which was predictable across doses and between single and repeat doses. The biological activity of atacicept was demonstrated by its marked effect in reducing B-cells and Ig levels in patients with SLE. This supports the utility of this therapeutic approach in the treatment of autoimmune diseases, such as SLE. PMID:19395457

  8. Perforation of the superior vena cava 5 days after insertion of a central venous catheter through the left internal jugular vein.

    PubMed

    Kurabe, Miyuki; Watanabe, Tatsunori; Kohno, Tatsuro

    2016-06-01

    We describe a very rare case of an indwelling central venous catheter (CVC) through the left internal jugular vein that perforated the superior vena cava (SVC) wall postoperatively, although the CVC was placed in the appropriate position preoperatively. Three days after CVC insertion, a chest radiograph showed that the CVC tip had moved from the lower SVC to the upper SVC. Five days after the insertion, computed tomography showed SVC perforation and the resulting hydrothorax. In cases of CVC insertion through the left side, the CVC tip should not be placed in the upper SVC (zone B). Considering individual clinical factors and the indwelling period for the CVC, the left innominate vein (zone C) may be a suitable site for the left-sided CVC tip to reduce the risk of SVC perforation.

  9. A preliminary study: aspirin discontinuation before elective operations; when is the optimal timing?

    PubMed Central

    Ozdemir, Suleyman; Ozis, Erpulat; Sahli, Zafer; Demirtas, Selda; Korkmaz, Atilla

    2013-01-01

    Purpose To evaluate the optimum timing of aspirin cessation before noncardiac surgeries. We have conducted a pilot study to minimize the aspirin cessation time before various surgeries. Methods Eighty patients who were taking regular aspirin for secondary prevention undergoing elective surgical operations were enrolled in the study. We separated the patients into two groups. The control group had 35 patients who stopped aspirin intake 10 days before surgery. The study group had 45 patients who stopped their aspirin intake and underwent surgery one day after arachidonic acid aggregation tests were within normal limits. Bleeding, blood loss, and transfusion requirements were assessed perioperatively. Results The mean time between aspirin cessation and aspirin nonresponsiveness were found to be 4.2 days with a median value of 4 days. In addition, the mean time between aspirin cessation and operation day were found to be 5.5 days with a median value of 5 days. No perioperative bleeding, thromboembolic or cardiovascular complications were encountered. Conclusion Reducing time of aspirin cessation from 7-10 days to 4-5 days is a possibility for patients using aspirin for secondary prevention without increased perioperative complications. PMID:24106686

  10. Toxicological Assessment of the Cochleate Derived from Neisseria meningitidis Proteoliposome in Sprague Dawley Rats

    PubMed Central

    Infante-Bourzac, Juan Francisco; Sifontes-Rodríguez, Sergio; Arencibia-Arrebola, Daniel Francisco; Hernández-Salazar, Tamara; Fariñas-Medina, Mildrey; Pérez, Oliver

    2012-01-01

    Background: The AFCo1 cochleate is a potential novel adjuvant derived from Neisseria meningitidis B proteoliposome. Aim: The aim was to assessing the safety of AFCo1 by single and repeated doses in Sprague Dawley rats. Materials and Methods: Rats were grouped for treatment with AFCo1, placebo formulation or control. The first study was a single intranasal dose of 100 μl and monitoring body weight, water, and food intakes as well as clinical symptoms. Fourteen days later the rats were killed and anatomopathological studies were conducted. In a second study, four similar doses of the test substance were instilled every 5 days. Clinical observations were carried out as for the single dose study and a number of rats from each group were killed 3 and 14 days after the last dose in order to conduct hematological, hemochemical, and anatomopathological studies. Results: No variable showed differences of toxicological relevance; the histological changes found were mild and similarly frequently in the three groups. According to the irritability index calculated form histology of the nasal region, AFCo1 was also classified as nonirritating. Conclusion: AFCo1 is potentially safe for human use by nasal route as evidenced by the absence of local and systemic signs of toxicity in Sprague Dawley rats. PMID:22454827

  11. Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

    PubMed Central

    Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

    2015-01-01

    TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats. PMID:26877840

  12. Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028 — For human safety in clinical study

    SciTech Connect

    Nishizato, Yohei; Imai, Satoki; Okahashi, Noriko; Yabunaka, Atsushi; Kunimatsu, Takeshi; Kikuchi, Kaoru; Yabuki, Masashi

    2014-05-01

    SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies. - Highlights: • SMP-028 inhibits neutral CEase more strongly than other steroidogenic enzymes in rats. • Inhibition of neutral CEase in rats by SMP-028 suppresses steroidogenesis in vivo. • SMP-028 does not inhibit neutral CEase in monkeys in vivo. • Steroidogenesis pathway in monkeys treated with SMP-028 was not suppressed. • SMP-028 may not inhibit LIPE in humans in vivo.

  13. Beef cattle body temperature during climatic stress: a genome-wide association study

    NASA Astrophysics Data System (ADS)

    Howard, Jeremy T.; Kachman, Stephen D.; Snelling, Warren M.; Pollak, E. John; Ciobanu, Daniel C.; Kuehn, Larry A.; Spangler, Matthew L.

    2014-09-01

    Cattle are reared in diverse environments and collecting phenotypic body temperature (BT) measurements to characterize BT variation across diverse environments is difficult and expensive. To better understand the genetic basis of BT regulation, a genome-wide association study was conducted utilizing crossbred steers and heifers totaling 239 animals of unknown pedigree and breed fraction. During predicted extreme heat and cold stress events, hourly tympanic and vaginal BT devices were placed in steers and heifers, respectively. Individuals were genotyped with the BovineSNP50K_v2 assay and data analyzed using Bayesian models for area under the curve (AUC), a measure of BT over time, using hourly BT observations summed across 5-days (AUC summer 5-day (AUCS5D) and AUC winter 5-day (AUCW5D)). Posterior heritability estimates were moderate to high and were estimated to be 0.68 and 0.21 for AUCS5D and AUCW5D, respectively. Moderately positive correlations between direct genomic values for AUCS5D and AUCW5D (0.40) were found, although a small percentage of the top 5 % 1-Mb windows were in common. Different sets of genes were associated with BT during winter and summer, thus simultaneous selection for animals tolerant to both heat and cold appears possible.

  14. Identification of phase-I metabolites and chronic toxicity study of the Kv1.3 blocker PAP-1 (5-(4-phenoxybutoxy)psoralen) in the rat.

    PubMed

    Hao, B; Chen, Z-W; Zhou, X-J; Zimin, P I; Miljanich, G P; Wulff, H; Wang, Y-X

    2011-03-01

    1. PAP-1 (5-(4-phenoxybutoxy)psoralen), a potent small-molecule blocker of the voltage-gated potassium Kv1.3 channel, is currently in preclinical development for psoriasis. This study was undertaken to identify the major phase I metabolites of PAP-1 in Sprague-Dawley (SD) rats. 2. Five phase I metabolites, that is 5-(oxybutyric-acid)psoralen (M1), 5-[4-(4-hydroxybutoxy)]psoralen (M2), 5-[4-(4-hydroxyphenoxy)butoxy]psoralen (M3), 5-[4-(3-hydroxyphenoxy)butoxy]psoralen (M4), and 8-hydroxyl-5-(4-phenoxybutoxy)psoralen (M5), were isolated from the bile of rats and identified by mass spectrometry and NMR spectroscopy. The last four metabolites are new compounds. 3. Incubation of PAP-1 with SD rat liver microsomes rendered the same five major metabolites in a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent manner suggesting that cytochrome P450 (CYP) enzymes are involved in PAP-1 metabolism. Inhibitors of rat CYP1A1/2 (alpha-naphthoflavone) and CYP3A (ketoconazole) but not CYP2D6 (quinidine), CYP2E (diethyldithiocarbamate), or CYP2C9 (sulphaphenazole) blocked the metabolism of PAP-1 in rat microsomes. 4. Of the five metabolites M3, M4, and M5 were found to inhibit Kv1.3 currents with nanomolar IC50s, while M1 and M2 were inactive. Our results identified the Kv1.3-inactive M1 as the major phase I metabolite, and suggest that hydroxylation and O-dealkylation are the major pathways of PAP-1 metabolism. 5. We further conducted a 6-month repeat-dose toxicity study with PAP-1 at 50 mg/kg in both male and female Lewis rats and did not observe any toxic effects.

  15. Pharmacokinetics of an Elevated Dosage of Micafungin in Premature Neonates

    PubMed Central

    Smith, P Brian; Walsh, Thomas J; Hope, William; Arrieta, Antonio; Takada, Akitsugu; Kovanda, Laura L; Kearns, Gregory L; Kaufman, David; Sawamoto, T; Buell, Donald N; Benjamin, Daniel K

    2009-01-01

    Background Determining the safety and pharmacokinetics of antifungal agents in neonates is important. A previous single-dose pharmacokinetic study of micafungin in neonates demonstrated that doses of 0.75 to 3 mg/kg produced lower plasma micafungin concentrations than in older patients because of increased apparent plasma clearance of micafungin in neonates. The primary objective of this study was to assess the safety and pharmacokinetics of an increased (15 mg/kg/day) dose of micafungin. Methods A repeated dose, open-label pharmacokinetic and safety trial of intravenous micafungin in 12 preterm neonates > 48 hours of life with suspected systemic infections. Neonates received 15 mg/kg/day of micafungin for 5 days. Blood samples were drawn relative to either the fourth or fifth dose. Systemic exposure was assessed by examination of the plasma area under the curve. Results The median birth weight and gestational age of the neonates were 775 g and 27 weeks, respectively. No adverse events related to micafungin were detected. The mean area under the curve and clearance for the cohort was 437.5 μg · h/mL and 0.575 mL/min/kg, respectively. The calculated clearance and volume of distribution for neonates was greater than that observed in older children and adults. Conclusions These data suggest that 15 mg/kg dosing in premature neonates corresponds to an exposure of approximately 5 mg/kg in adults. No adverse events related to micafungin were observed. PMID:19319022

  16. AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects.

    PubMed

    Jucaite, Aurelija; Takano, Akihiro; Boström, Emma; Jostell, Karl-Gustav; Stenkrona, Per; Halldin, Christer; Segerdahl, Märta; Nyberg, Svante

    2013-07-01

    The histamine H3 receptor represents an appealing central nervous system drug target due to its important role in the neurobiology of cognition and wake-sleep regulation. The therapeutic benefit of H3 antagonists/inverse agonists may be hampered by disruption of sleep that has been observed in humans with prolonged high H3 receptor occupancy (H3RO), extending into night-time. AZD5213 is a highly selective H3 antagonist (in vitro inverse agonist) developed to achieve a pharmacokinetic profile permitting circadian fluctuations of H3RO. Its efficacy has been demonstrated in rodent behavioural models of cognition. In human subjects, AZD5213 was safe and well tolerated following repeated doses (1-14 mg/d) and demonstrated a short (∼5 h) half-life. In this PET study H3RO was measured using the radioligand [11C]GSK189254 ([11C]AZ12807110) in seven young male volunteers following single doses of AZD5213 (0.05-30 mg). H3RO was calculated using the Lassen plot method. The plasma concentrations and the affinity constant (K i,pl 1.14 nmol/l, corresponding to the plasma concentration required to occupy 50% of available receptors) were used to estimate the H3RO time-course. AZD5213 showed dose and concentration dependent H3RO ranging from 16 to 90%. These binding characteristics and the pharmacokinetic profile of AZD5213 indicate that high daytime and low night-time H3RO could be achieved following once daily oral dosing of AZD5213. Fluctuations of H3RO following circadian rhythm of the histamine system may be expected to reduce the risk of sleep disruption while maintaining daytime efficacy. AZD5213 may thus be an optimal compound to evaluate the clinical benefit of selective H3 antagonism in cognitive disorders.

  17. Safety evaluation of ABELCET, an amphotericin B lipid complex (ABLC): toxicity studies in rats.

    PubMed

    Zhang, Zhihua; Diener, Robert M; Lipman, Jack M

    2006-01-01

    ABELCET (ABLC) is a widely used amphotericin B lipid complex formulation that is approved for use in the treatment of invasive fungal infections in patients who are refractory or intolerant of conventional amphotericin B (AmB). The safety profile of ABLC has been characterized in two acute and two repeat-dose toxicity studies in rats. The acute toxicity studies indicated that single intravenous doses of ABLC are at least 20 times less toxic than conventional amphotericin B doses without the lipid formulation, Fungizone. Intravenous doses of 0, 1, 3, or 10 mg/kg/day to groups of rats (10 to 15 rats/sex/group) for 31 days elicited no mortality or overt clinical signs of toxicity, whereas alternate intravenous/intraperitoneal doses (three each per week) for 6 months, produced one death in the control group, one in the intermediate-dose group, and two in the high-dose group. Clinical signs (predominantly piloerection and hunched posture at 10 mg/kg/day) were attributed to granulomatous inflammatory lesions in the abdominal wall, mesentery, and omentum, which were produced by the intraperitoneal injections of ABLC. Feed consumption and body weight gains decreased in high-dose male rats in the one-month study and were significantly lower in male rats at 3 and 10 mg/kg/day in the 6-month study. In contrast, water consumption increased in male and female rats in both studies. Trends of minimal to moderate, dose-related increases in relative kidney, liver and spleen weights, and histological evidence of hypertrophy and hyperplasia of reticuloendothelial cells in the liver and spleen and mild, dose-related impairment of renal function occurred in both the 1- and 6-month studies. Examination of high-dose rats following a recovery period of 28 days after completion of 31 days of dosing suggested that treatment-related changes were reversible. The observed changes for ABLC are similar to those for other amphotericin B lipid formulations, such as AmBisome (LAmB), except for the

  18. Ultraviolet studies of Cepheids

    NASA Technical Reports Server (NTRS)

    Boehm-Vitense, Erika

    1992-01-01

    We discuss whether with new evolutionary tracks we still have a problem fitting the Cepheids and their evolved companions on the appropriate evolutionary tracks. We find that with the Bertelli et al. tracks with convective overshoot by one pressure scale height the problem is essentially removed, though somewhat more mixing would give a better fit. By using the results of recent nonlinear hydrodynamic calculations, we find that we also have no problem matching the observed pulsation periods of the Cepheids with those expected from their new evolutionary masses, provided that Cepheids with periods less than 9 days are overtone pulsators. We investigate possible mass loss of Cepheids from UV studies of the companion spectrum of S Mus and from the ultraviolet spectra of the long period Cepheid l Carinae. For S Mus with a period of 9.6 days we derive an upper limit for the mass loss of M less than 10(exp -9) solar mass, if a standard velocity law is assumed for the wind. For l Carinae with a period of 35.5 days we find a probable mass loss of M is approximately 10(exp -5+/-2) solar mass.

  19. Topical formulations containing finasteride. Part I: in vitro permeation/penetration study and in vivo pharmacokinetics in hairless rat.

    PubMed

    Monti, Daniela; Tampucci, Silvia; Burgalassi, Susi; Chetoni, Patrizia; Lenzi, Carla; Pirone, Andrea; Mailland, Federico

    2014-08-01

    In hair follicle (Hf) cells, the type-2 5-α-reductase enzyme, implicated in androgenetic alopecia, is selectively inhibited by finasteride (FNS). Because an effective topical formulation to deliver FNS to Hf is currently unavailable, this investigation aimed at evaluating in vitro FNS skin permeation and retention through and into hairless rat and human abdominal skin. Four hydroxypropyl chitosan (HPCH)-based formulations (P-08-012, P-08-016, P-08-063, and P-08-064) and one anhydrous formulation without HPCH (P-10-008) were tested. The pharmacokinetics in plasma and skin after application of P-08-016 or P-10-008 on dorsal rat skin with single and repeated doses was investigated. P-08-016 performed the best in driving FNS to the reticular dermis without producing a high transdermal flux. Neither the in vivo single nor the repeated dose experiments produced plasma levels of FNS and no differences were found between formulations concerning skin retention. No increase in the amount of drug retained in the skin was obtained with the repeated dose experiment. In conclusion, the HPCH-based formulation P-08-016 might represent an alternative to systemic therapy for its ability to promote a cutaneous depot of FNS in the region of hair bulbs, minimizing systemic absorption even after repeated treatments.

  20. Absence of in vivo genotoxicity of 3-monochloropropane-1,2-diol and associated fatty acid esters in a 4-week comprehensive toxicity study using F344 gpt delta rats.

    PubMed

    Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Horibata, Katsuyoshi; Ishii, Yuji; Umemura, Takashi; Honma, Masamitsu; Nohmi, Takehiko; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2014-07-01

    3-Monochloropropane-1,2-diol (3-MCPD) is regarded as a rat renal and testicular carcinogen and has been classified as a possible human carcinogen (group 2B) by International Agency for Research on Cancer. This is potentially of great importance given that esters of this compound have recently found to be generated in many foods and food ingredients as a result of food processing. There have been a few reports about their toxicity, although we have recently found that the toxicity profile of 3-MCPD esters was similar to that of 3-MCPD in a rat 13-week repeated dose study, except for the acute renal toxicity seen in 3-MCPD-treated females. In the present study, to examine in vivo genotoxicity we administered equimolar doses of 3-MCPD or 3-MCPD fatty acid esters (palmitate diester, palmitate monoester and oleate diester) to 6-week-old male F344 gpt delta rats carrying a reporter transgene for 4 weeks by intragastric administration. In vivo micronucleus, Pig-a mutation and gpt assays were performed, as well as investigations of major toxicological parameters including histopathological features. As one result, the relative kidney weights of the 3-MCPD and all three ester groups were significantly increased compared with the vehicle control group. However, the frequency of micronucleated reticulocytes and Pig-a mutant red blood cells did not differ among groups. Moreover, no changes were observed in mutant frequencies of gpt and red/gam (Spi(-)) genes in the kidney and the testis of 3-MCPD and 3-MCPD-fatty-acid-esters-treated rats. In histopathological analyses, no treatment related changes were observed, except for decrease of eosinophilic bodies in the kidneys of all treated groups. These results suggest that 3-MCPD and its fatty acid esters are not in vivo genotoxins, although they may exert renal toxicity.

  1. A safety study of a novel photosensitizer, sinoporphyrin sodium, for photodynamic therapy in Beagle dogs.

    PubMed

    Lin, Ni; Li, Chao; Wang, Zhonghua; Zhang, Jingxuan; Ye, Xiangfeng; Gao, Wenjing; Wang, Aiping; Jin, Hongtao; Wei, Jinfeng

    2015-04-01

    Sinoporphyrin sodium (DVDMS) is a novel hematoporphyrin-like photosensitizer developed for photodynamic therapy (PDT), an effective therapeutic modality for tumor treatment; however, the safety of photosensitizer-based PDT is always of great concern. The purpose of the current study was to investigate the potential repeated-dose toxicity and describe the toxicokinetic process of DVDMS-based PDT in Beagle dogs. The dogs were randomly allocated to six groups, and then were administrated a DVDMS preparation intravenously at dose levels of 0, 1, 3, 9, 1 and 9 mg per kg body weight, respectively; then, the latter two groups were illuminated 24 h later with a 630 nm laser for 10 min, once every seven days for 5 weeks. During the study period, clinical signs, mortality, body weight, food consumption, body temperature, ophthalmoscopy, hematology, serum biochemistry, urinalysis, electrocardiograms, toxicokinetics, organ weights, gross anatomy and histopathology were examined. After the administration, no deaths were observed; however, the dogs that received PDT showed skin swelling and ulceration, indicating that DVDMS-PDT induced a phototoxic effect. DVDMS led to an increase in blood coagulation in dogs in the 9 mg kg(-1) group and in the two PDT groups on Day 35, whereas it induced a decrease in dogs in the 3 mg kg(-1) group and in the two PDT groups on Day 49. The toxicokinetic study showed that the systematic exposure of DVDMS in dogs occurred in a dose-dependent manner, and DVDMS did not accumulate in blood plasma. The DVDMS-based PDT group showed no obvious treatment-related pathological changes; however, slight or mild brown-and-yellow pigmentation of DVDMS (or its metabolite) was observed to deposit in the liver, spleen, local lymph nodes and marrow of dogs in the mid- and high-dose groups, as well as the high-dose PDT group. In females, the absolute and relative spleen weights increased in dogs in the 9 mg kg(-1) DVDMS groups with and without PDT during the

  2. Synchrotron studies of narrow band materials

    SciTech Connect

    Not Available

    1992-01-01

    Since last year, we have had three 3-week blocks of beamtime, in April and November 1991 and February 1992, on the Ames/Montana beamline at the Wisconsin Synchrotron Radiation Center (SRC). These runs continued our program on high temperature superconductors, heavy Fermion and related uranium and rare earth materials, and started some work on transition metal oxides. We have also had beamtime at the Brookhaven NSLS, 5 days of beamtime on the Dragon monochromator, beamline U4B, studying resonant photoemission of transition metal oxides using photon energies around the transition metal 2p edges. Data from past runs has been analyzed, and in some cases combined with photoemission and bremsstrahlung isochromat spectroscopy (BIS) data taken in the home U-M lab. 1 fig.

  3. Uterine rupture and septic peritonitis following dystocia and assisted delivery in a Great Dane bitch.

    PubMed

    Humm, Karen R; Adamantos, Sophie E; Benigni, Livia; Armitage-Chan, Elizabeth A; Brockman, Daniel J; Chan, Daniel L

    2010-01-01

    A Great Dane bitch was treated for presumed primary uterine inertia with repeated doses of oxytocin and manually assisted whelping. She was diagnosed with uterine rupture and septic peritonitis the following day. The uterine rupture is hypothesized to have occurred as a result of the management strategy used to treat dystocia. The dog underwent ovariohysterectomy, and the septic peritonitis was managed with open peritoneal drainage. The dog recovered well and was discharged 5 days later. No previous reports of canine uterine rupture associated with manual intervention appear to have been published. This report highlights the potential dangers involved in such an approach.

  4. Influence of CYP2D6-dependent metabolism on the steady-state pharmacokinetics and pharmacodynamics of metoprolol and nicardipine, alone and in combination.

    PubMed Central

    Laurent-Kenesi, M A; Funck-Brentano, C; Poirier, J M; Decolin, D; Jaillon, P

    1993-01-01

    1 The metabolism of metoprolol depends in part on the genetically determined activity of the CYP2D6 isoenzyme. In vitro studies have shown that nicardipine is a potent inhibitor of CYP2D6 activity. Since the combination of metoprolol and nicardipine is likely to be used for the treatment of hypertension, we examined the interaction between these two drugs at steady-state. 2 Fourteen healthy volunteers, seven extensive and seven poor metabolisers of dextromethorphan were studied in a double-blind, randomised cross-over four-period protocol. Subjects received nicardipine 50 mg every 12 h, metoprolol 100 mg every 12 h, a combination of both drugs and placebo during 5.5 days. Steady-state pharmacokinetics of nicardipine and metoprolol were analyzed. Beta-adrenoceptor blockade was assessed as the reduction of exercise-induced tachycardia. 3 During treatment with metoprolol, alone or in combination with nicardipine, its steady-state plasma concentrations were higher in subjects of the poor metaboliser phenotype than in extensive metabolisers. Beta-adrenoceptor blockade was also more pronounced in poor metabolisers than in extensive metabolisers of dextromethorphan during treatment with metoprolol alone or in combination with nicardipine (24.0 +/- 2.4% vs 17.1 +/- 3.5% and 24.1 +/- 2.5% vs 15.4 +/- 2.7% reduction in exercise trachycardia, respectively, P < 0.01 in each case). 4 Nicardipine produced a small increase in plasma metoprolol concentration in extensive metabolisers from 35.9 +/- 16.6 to 45.8 +/- 15.4 ng ml(-1) (P < 0.02), but had no significant effect in poor metabolisers. However, nicardipine did not alter the R/S metoprolol ratio in plasma 3 h after dosing, the plasma concentration of S-(-)-metoprolol 3 h after dosing or the beta-adrenoceptor blockade produced by metoprolol in subjects of both phenotypes. The partial metabolic clearance of metoprolol to alpha-hydroxy-metoprolol was not altered significantly in extensive metabolisers. Plasma nicardipine

  5. Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study.

    PubMed Central

    Amir, J.; Harel, L.; Smetana, Z.; Varsano, I.

    1997-01-01

    OBJECTIVES: To examine the efficacy of aciclovir suspension for treating herpetic gingivostomatitis in young children. DESIGN: Randomised double blind placebo controlled study. SETTING: Day care unit of a tertiary paediatric hospital. SUBJECTS: 72 children aged 1-6 years with clinical manifestations of gingivostomatitis lasting less than 72 hours; 61 children with cultures positive for herpes simplex virus finished the study. MAIN OUTCOME MEASURES: Duration of oral lesions, fever, eating and drinking difficulties, and viral shedding. INTERVENTION: Aciclovir suspension 15 mg/kg five times a day for seven days, or placebo. RESULTS: Children receiving aciclovir had oral lesions for a shorter period than children receiving placebo (median 4 v 10 days (difference 6 days, 95% confidence interval 4.0 to 8.0)) and earlier disappearance of the following signs and symptoms: fever (1 v 3 days (2 days, 0.8 to 3.2)); extraoral lesions (lesions around the mouth but outside the oral cavity) (0 v 5.5 days (5.5 days, 1.3 to 4.7)); eating difficulties (4 v 7 days (3 days, 1.31 to 4.69)); and drinking difficulties (3 v 6 days (3 days, 1.1 to 4.9)). Viral shedding was significantly shorter in the group treated with aciclovir (1 v 5 days (4 days, 2.9 to 5.1)). CONCLUSIONS: Oral aciclovir treatment for herpetic gingivostomatitis, started within the first three days of onset, shortens the duration of all clinical manifestations and the infectivity of affected children. Further studies are needed to evaluate the ideal dose and length of treatment. PMID:9224082

  6. RIFM fragrance ingredient safety assessment, Fenchyl alcohol, CAS registry number 1632-73-1.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Shen, J; Schultz, T W; Sipes, I G; Wall, B; Wilcox, D K

    2015-10-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 15 mg/kg/day. A gavage 13-week subchronic toxicity study conducted in rats on a suitable read across analog resulted in a MOE of 10,714 while assuming 100% absorption from skin contact and inhalation. A MOE of >100 is deemed acceptable.

  7. RIFM fragrance ingredient safety assessment, Isoborneol, CAS Registry Number 124-76-5.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

    2015-10-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential as well as environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NOAEL of 15 mg/kg/day based on a gavage 13-week subchronic toxicity study conducted in rats on a read across analog resulting in a MOE of 1000 considering 100% absorption from skin contact and inhalation. A MOE of >100 is deemed acceptable.

  8. RIFM fragrance ingredient safety assessment, isoamyl salicylate, CAS registry number 87-20-7.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

    2015-10-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined using to have the most conservative systemic exposure derived NOAEL of 47 mg/kg/day. A dietary 13-week subchronic toxicity study conducted in rats on a suitable read across analog resulted in a MOE of 2350 while considering 10.3% absorption from skin contact and 100% from inhalation. A MOE of >100 is deemed acceptable.

  9. RIFM fragrance ingredient safety assessment, α-butylcinnamaldehyde, CAS Registry Number 7492-44-6.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

    2015-10-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 29.9 mg/kg/day. A dietary 14-week subchronic toxicity study conducted in rats on a suitable read across analog resulted in a MOE of 3784810 while considering 9.54% absorption from skin contact and 100% from inhalation. A MOE of > 100 is deemed acceptable.

  10. RIFM fragrance ingredient safety assessment, 2-methyl-3-buten-2-ol, CAS Registry Number 115-18-4.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Shen, J; Schultz, T W; Sipes, I G; Wall, B; Wilcox, D K

    2015-10-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential as well as environmental safety. Repeated dose, developmental, and reproductive toxicities were determined to have the most conservative systemic exposure derived NO[A]EL of 50 mg/kg/day, based on OECD gavage toxicity studies in rats, that resulted in a MOE of 4545455 after considering 100% absorption from skin contact and inhalation. A MOE of >100 is deemed acceptable.

  11. RIFM fragrance ingredient safety assessment, Benzyl propionate, CAS Registry Number 122-63-4.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

    2016-11-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 14.5 mg/kg/day. A dietary 2-year chronic toxicity study conducted in rats on a suitable read across analog resulted in a MOE of 1318 while considering 78.7% absorption from skin contact and 100% from inhalation. A MOE of >100 is deemed acceptable.

  12. RIFM fragrance ingredient safety assessment, isoeugenol, CAS Registry Number 97-54-1.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

    2016-11-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 37.5 mg/kg/day. A gavage 13-week subchronic toxicity study conducted in mice resulted in a MOE of 5769 while considering 38.4% absorption from skin contact and 100% from inhalation. A MOE of >100 is deemed acceptable.

  13. RIFM fragrance ingredient safety assessment, α-Ionone, CAS Registry Number 127-41-3.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

    2016-11-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined to have the most conservative systemic exposure derived NO[A]EL of 10 mg/kg/day. A dietary 90-day subchronic toxicity study conducted in rats resulted in a MOE of 182 while assuming 100% absorption from skin contact and inhalation. A MOE of >100 is deemed acceptable.

  14. RIFM fragrance ingredient safety assessment, l-linalool, CAS Registry Number 126-91-0.

    PubMed

    Api, A M; Belsito, D; Bhatia, S; Bruze, M; Calow, P; Dagli, M L; Dekant, W; Fryer, A D; Kromidas, L; La Cava, S; Lalko, J F; Lapczynski, A; Liebler, D C; Miyachi, Y; Politano, V T; Ritacco, G; Salvito, D; Schultz, T W; Shen, J; Sipes, I G; Wall, B; Wilcox, D K

    2016-11-01

    The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Repeated dose toxicity was determined using a suitable read across analog to have the most conservative systemic exposure derived NO[A]EL of 36 mg/kg/day. A dermal 90-day subchronic toxicity study conducted in rats resulted in a MOE of 2250 while considering 14.4% absorption from skin contact and 100% from inhalation. A MOE of >100 is deemed acceptable.

  15. Efficacy, Safety, and Dose of Pafuramidine, a New Oral Drug for Treatment of First Stage Sleeping Sickness, in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies

    PubMed Central

    Burri, Christian; Yeramian, Patrick D.; Merolle, Ada; Serge, Kazadi Kyanza; Mpanya, Alain; Lutumba, Pascal; Mesu, Victor Kande Betu Ku; Lubaki, Jean-Pierre Fina; Mpoto, Alfred Mpoo; Thompson, Mark; Munungu, Blaise Fungula; Josenando, Théophilo; Bernhard, Sonja C.; Olson, Carol A.; Blum, Johannes; Tidwell, Richard R.; Pohlig, Gabriele

    2016-01-01

    Background Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT. Methods The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent. Findings/Conclusion Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3. PMID:26881924

  16. Aqueous extract of Senecio candicans DC induce liver and kidney damage in a sub-chronic oral toxicity study in Wistar rats.

    PubMed

    Lakshmanan, Hariprasath; Raman, Jegadeesh; Pandian, Arjun; Kuppamuthu, Kumaresan; Nanjian, Raaman; Sabaratam, Vikineswary; Naidu, Murali

    2016-08-01

    Senecio candicans DC. (Asteraceae) is used as a remedy for gastric ulcer and stomach pain in the Nilgiris, district, Tamil Nadu. The present investigation was carried out to evaluate the sub-chronic toxicity of an aqueous extract of Senecio candicans (AESC) plant in Wistar albino rats. The study was conducted in consideration of the OECD 408 study design (Repeated Dose 90-Day Oral Toxicity Study in Rodents) and the extract was administered via gavage at doses of 250, 500 or 750 mg/kg body weight per day for 90-days. Hematological, biochemical parameters were determined on days 0, 30, 60 and 90 of administration. Animals were euthanized after 90 d treatment and its liver and kidney sections were taken for histological study. The results of sub-chronic study showed significant increase (P < 0.05) in serum uric acid, creatinine, aspartate transaminase (AST) and alanine transaminase (ALP) levels. Histological examination of liver showed mild mononuclear infiltration in the portal trait, enlarged nucleus around the central vein and mild loss of hepatocyte architecture in rats treated with 750 mg/kg of AESC. Histological examination of kidney showed focal interstitial fibrosis, crowding of glomeruli and mild hydropic change with hypercellular glomeruli in rats treated with 750 mg/kg of AESC. However, no remarkable histoarchitectural change in hepatocytes and glomeruli were observed in rats treated with lower concentrations (250 and 500 mg/kg b.w.) of AESC compared to control group animals. The no-observed adverse effect level (NOAEL) of AESC in the present study was 500 mg/kg b.w. Signs of toxic effects are evident from the current study. Although AESC contains low concentrations of PA, findings from this study suggest that regular consumers of herbal remedies derived from this plant may develop kidney and liver toxicity. Further studies on the isolation and characterization of PAs are necessary to determine the safe dose level of the extract for therapeutic use

  17. A Pilot Study to Examine Maturation of Body Temperature Control in Preterm Infants

    PubMed Central

    Knobel, Robin B.; Levy, Janet; Katz, Laurence; Guenther, Bob; Holditch-Davis, Diane

    2013-01-01

    Objective To test instrumentation and develop analytic models to use in a larger study to examine developmental trajectories of body temperature and peripheral perfusion from birth in extremely low birth weight (EBLW) infants. Design A case study design. Setting The study took place in a level four neonatal intensive care unit (NICU) in North Carolina. Participants Four ELBW infants, less than 29 weeks gestational age at birth. Methods Physiologic data were measured every minute for the first 5 days of life: peripheral perfusion using perfusion index by Masimo and body temperature using thermistors. Body temperature was also measured using infrared thermal imaging. Stimulation and care events were recorded over the first 5 days using video which was coded with Noldus Observer software. Novel analytical models using the state space approach to time series analysis were developed to explore maturation of neural control over central and peripheral body temperature. Results/Conclusion Results from this pilot study confirmed the feasibility of using multiple instruments to measure temperature and perfusion in ELBW infants. This approach added rich data to our case study design and set a clinical context with which to interpret longitudinal physiological data. PMID:24004312

  18. Data collection for a time-of-travel and dispersion study on the Coosa River near Childersburg, Alabama

    USGS Publications Warehouse

    Gardner, R.A.

    1985-01-01

    Approximately 2,300 dye-tracer samples were collected and analyzed during a 5-day time-of-travel study on a 23-mile reach of the Coosa River between Logan Martin and Lay dams near Childersburg, Alabama, October 27 to 31, 1984. Rhodamine WT was used as the tracer-dye. Unsteady flow conditions prevailed in the study reach. The rate of movement of the dye cloud between sampling cross sections ranged from 0.15 to 1.36 feet per second. The average rate of movement of the dye cloud between the injection cross section and the downstream sampling cross section was 0.42 foot per second. (USGS)

  19. Studying RR Lyrae Stars in M4 with K2

    NASA Astrophysics Data System (ADS)

    Kuehn, Charles A.; Drury, Jason; Moskalik, Pawel

    2017-01-01

    Observations by Kepler/K2 have revolutionized the study of RR Lyrae stars by allowing the detection of new phenomena, such as low amplitude additional modes and period doubling, which had not previously been seen from the ground. During its campaign 2, K2 observed the globular cluster M4, providing the first opportunity to study a sizeable group of RR Lyrae stars that belong to a single population; the other RR Lyrae stars that have been observed from space are field stars in the galactic halo and thus belong to an assortment of populations. We present the results of our study of the RR Lyrae variables in M4 from K2 photometry. We have identified additional, low amplitude pulsation modes in the two observed RRc stars. In three RRab stars we have found the Blazhko effect with periods of 16.6 days, 22.4 days, and 44.5 days.

  20. Global normal mode planetary wave activity: a study using TIMED/SABER observations from the stratosphere to the mesosphere-lower thermosphere

    NASA Astrophysics Data System (ADS)

    John, Sherine Rachel; Kumar, Karanam Kishore

    2016-12-01

    A comprehensive study of three normal mode travelling planetary waves, namely the quasi-16, -10 and -5 day waves, is carried out globally using 5 years (2003-2007) of TIMED/SABER temperature measurements from the stratosphere to the mesosphere-lower thermosphere (MLT) by employing the two dimensional Fourier decomposition technique. From preliminary analysis, it is found that significant amplitudes of normal modes are confined to wave numbers-2 (westward propagating modes) to 2 (eastward propagating modes). The westward propagating quasi 16-day waves with zonal wave number 1 (W1; W1 refers to westward propagating wave with zonal wave number 1) peaks over winter-hemispheric high latitudes with northern hemisphere (NH) having higher amplitudes as compared to their southern hemispheric (SH) counterpart. The W1 quasi 16-day waves exhibit a double peak structure in altitude over winter hemispheric high latitudes. The eastward propagating quasi 16-day waves with wave number 1 (E1; E1 refers to eastward propagating wave with zonal wave number 1) exhibits similar features as that of W1 waves in the NH. In contrast, the E1 quasi 16-day waves in the SH show larger amplitudes as compared to the W1 waves and they do not exhibit double peak structure in altitude. Similar to the quasi 16-day waves, the quasi 10- and 5-day wave amplitudes with respect to their wavenumbers are delineated. Unlike quasi-16 and -10 day waves, quasi-5 day waves peak during vernal equinox both in the SH and NH. The peak activity of the W1 quasi-5 day wave is centered around 40°N and 40°S exhibiting symmetry with respect to the equator. A detailed discussion on the height-latitude structure, interannual variability and inter-hemispheric propagation of quasi 16-, 10- and 5-day waves are discussed. The significance of the present study lies in establishing the 5-year climatology of normal mode planetary waves from the stratosphere to the MLT region including their spatial-temporal evolution, which are

  1. Randomized, double-blind, comparative study of oral metronidazole and tinidazole in treatment of bacterial vaginosis

    PubMed Central

    Raja, Indu M.; Basavareddy, Asha; Mukherjee, Deepali; Meher, Bikash Ranjan

    2016-01-01

    Objective: To compare the efficacy and tolerability of oral metronidazole and tinidazole in patients with bacterial vaginosis (BV) using Amsel's criteria. Patients and Methods: This was a randomized double-blind study, conducted by the Departments of Pharmacology and Gynecology of a tertiary care teaching hospital. Patients diagnosed with BV received either tablet metronidazole 500 mg twice daily for 5 days or tablet tinidazole 500 mg once daily + one placebo for 5 days and instructed to come for follow-up at the 1st week and 4th week. They were categorized as cured, partially cured, and not cured based on Amsel's criteria at the end of the study and compared between two groups using Chi-square test. Results: A total 120 women were enrolled in the study, of which 114 completed the study. The treatment arms were comparable. The cure rate with low-dose tinidazole was significantly more compared to metronidazole at 4th week (P = 0.0013), but not at 1st week (P = 0.242). The adverse drug reactions were less with tinidazole compared to metronidazole. Conclusion: Tinidazole at lower dose offers a better efficacy than metronidazole in long-term cure rates and in preventing relapses with better side effect profile. PMID:28066102

  2. Impact of the ongoing Amazonian deforestation on local precipitation: A GCM simulation study

    SciTech Connect

    Walker, G.K.; Sud, Y.C.; Atlas, R.

    1995-03-01

    Numerical simulation experiments were conducted to delineate the influence of in situ deforestation data on episodic rainfall by comparing two ensembles of five 5-day integrations performed with a recent version of the Goddard Laboratory for Atmospheres GCM that has a simple biosphere model (SiB). The first set, called control cases, used the standard SiB vegetation cover (comprising 12 biomes) and assumed a fully forested Amazonia, while the second set, called deforestation cases, distinguished the partially deforested regions of Amazonia as savanna. Except for this difference, all other initial and prescribed boundary conditions were kept identical in both sets of integrations. The differential analyses of these five cases show the following local effects of deforestation. (1) A discernible decrease in evapotranspiration of about 0.80 mm d{sup {minus}1} (roughly 18%) that is quite robust in the averages for 1-, 2-, and 5-day forecasts. (2) A decrease in precipitation of about 1.18 mm d{sup {minus}1} (roughly 8%) that begins to emerge even in 1-2-day averages and exhibits complex evolution that extends downstream with the winds. A larger decrease in precipitation as compared to evapotranspiration produces some drying and warming. The precipitation differences are consistent with the decrease in atmospheric moisture flux convergence and are consistent with earlier simulation studies of local climate change due to large-scale deforestation. (3) A significant decrease in the surface drag force (as a consequence of reduced surface roughness of deforested regions) that, in turn, affects the dynamical structure of moisture convergence and circulation. The surface winds increase significantly during the first day, and thereafter the increase is well maintained even in the 2- and 5-day averages. 34 refs., 9 figs., 2 tabs.

  3. 76 FR 82146 - Tepraloxydim; Pesticide Tolerances

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-30

    ... toxicity study, fetal effects (reduced fetal body weights, delayed ossification and the occurrence of... subgroup 20B''. BASF Corporation requested these tolerances under the Federal Food, Drug, and Cosmetic Act... effect levels) established in repeat-dose mouse, rat and dog studies). Reproductive effects...

  4. 77 FR 27130 - Ametoctradin; Pesticide Tolerances

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-09

    ... studies to human risk. EPA has also considered available information concerning the variability of the... with ametoctradin, no single dose or repeated dose study performed by any route of exposure produced a significant toxic effect up to or within 75-80% of the limit dose (1000 mg/kg/day). This includes the...

  5. REVIEW: ASSESSING THE POTENTIAL TO INDUCE RESPIRATORY HYPERSENSITIVITY

    EPA Science Inventory

    The respiratory tract has been long recognized as an important target organ in the safety assessment of drugs and chemicals, as well as protein- or peptide-based products. Indeed, acute and repeat dose inhalation studies have been an important part of guideline studies throughou...

  6. 75 FR 81878 - Imazosulfuron; Pesticide Tolerances

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-29

    ... primary target organ of imazosulfuron in repeated-dose studies was the liver in all species tested. Mild... fed > 1,000 mg/kg/day beginning at 3 months in the chronic toxicity/ carcinogenicity study. Ocular... limit dose and the primary toxic and intermediate-term (1 to 6 effects of concern (liver, eye)...

  7. National guidelines for outbreak investigation: an evaluation study.

    PubMed

    Fararouei, M; Rezaee, S; Shirazi, A Raigan; Naghmachi, M; Shirazi, K Karimzadeh; Jamshidi, A; Jafari, J

    2013-09-01

    This paper reports an independent epidemiological study to evaluate the validity of the results of an official investigation into an outbreak of gastroenteritis at a university campus in Yasuj, central-south Islamic Republic of Iran. The official report of the outbreak by the Department for Disease Control at the provincial health centre found only 65 cases over a 5-day period, all females, living in the student halls of residence. This contrasts with a questionnaire survey of 963 students at the same university, which found 395 students (192 males and 203 females), living in residences and at home, who reported at least 1 gastrointestinal symptom over a 12-week period. Within this period at least 2 outbreaks occurred. Such a large discrepancy between the official report and the current study suggests that the health services and the public may have been misled about the proper response to the outbreak.

  8. Phase I study of NKT-01.

    PubMed

    Tamura, K; Niitani, H; Oguro, M; Ohno, R; Sanpi, K; Majima, H; Masaoka, T; Kimura, I; Inagaki, J; Suzuoki, Y

    1995-01-01

    A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20-500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the alpha and beta phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In

  9. Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

    SciTech Connect

    Qi, Yanxin; Guo, Huanhuan; Hu, Ningning; He, Dongyun; Zhang, Shi; Chu, Yunjie; Huang, Yubin; Li, Xiao; Sun, LiLi; Jin, Ningyi

    2014-10-15

    Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10{sup 10} VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10{sup 10} VP/kg) and beagles (2.5 × 10{sup 9} VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10{sup 10} VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10{sup 8} VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad

  10. Polarized electric field effects on the regulation of succinate dehydrogenase activity in amphibian muscle and liver: kinetic study.

    PubMed

    Subrahamanyam, K; Reddy, G R; Babu, G R; Chetty, C S

    1989-04-01

    Electropolarity treatment (0.8 V/DC/Cm) was given to the gastrocnemius muscle of Bufo melanostictus every day for 5 min. for 5 days, and kinetic study of succinate dehydrogenase (SDH) in muscle and liver was conducted with different effectors - sodium malonate, ethylene diamine tetra acetic acid (EDTA), calcium chloride (CACl2) and sodium citrate. Of the four modulators tested, the malonate and EDTA inhibited while sodium citrate and CACl2 activated the enzyme. The significance of the modulation in SDH activity to different extents was discussed.

  11. Acute and subchronic oral toxicity studies in rats with nanoscale and pigment grade titanium dioxide particles.

    PubMed

    Warheit, D B; Brown, S C; Donner, E M

    2015-10-01

    Data generated using standardized testing protocols for toxicity studies generally provide reproducible and reliable results for establishing safe levels and formulating risk assessments. The findings of three OECD guideline-type oral toxicity studies of different duration in rats are summarized in this publication; each study evaluated different titanium dioxide (TiO2) particles of varying sizes and surface coatings. Moreover, each study finding demonstrated an absence of any TiO2 -related hazards. To briefly summarize the findings: 1) In a subchronic 90-day study (OECD TG 408), groups of young adult male and female rats were dosed with rutile-type, surface-coated pigment-grade TiO2 test particles (d50 = 145 nm - 21% nanoparticles by particle number criteria) by oral gavage for 90 days. The no-adverse-effect level (NOAEL) for both male and female rats in this study was 1000 mg/kg bw/day, the highest dose tested. The NOAEL was determined based on a lack of TiO2 particle-related adverse effects on any in-life, clinical pathology, or anatomic/microscopic pathology parameters; 2) In a 28-day repeated-dose oral toxicity study (OECD TG 407), groups of young adult male rats were administered daily doses of two rutile-type, uncoated, pigment-grade TiO2 test particles (d50 = 173 nm by number) by daily oral gavage at a dose of 24,000 mg/kg bw/day. There were no adverse effects measured during or following the end of the exposure period; and the NOAEL was determined to be 24,000 mg/kg bw/day; 3) In an acute oral toxicity study (OECD TG 425), female rats were administered a single oral exposure of surface-treated rutile/anatase nanoscale TiO2 particles (d50 = 73 nm by number) with doses up to 5000 mg/kg and evaluated over a 14-day post-exposure period. Under the conditions of this study, the oral LD50 for the test substance was >5000 mg/kg bw. In summary, the results from these three toxicity studies - each with different TiO2 particulate-types, demonstrated an absence of

  12. 78 FR 27860 - Revocation of TSCA Section 4 Testing Requirements for One High Production Volume Chemical Substance

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-13

    ... invertebrate) and toxicity to algae has not been satisfied by existing studies, and that the fish acute... include tests for octanol/water partition coefficient, acute toxicity to Daphnia, toxicity to algae, and... Daphnia, toxicity to algae, and combined 28-day repeated-dose toxicity with a...

  13. 77 FR 28340 - Revocation of TSCA Section 4 Testing Requirements for One High Production Volume Chemical Substance

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-14

    ... toxicity to algae had not been satisfied by existing studies, and that the fish acute toxicity test... include tests for octanol/water partition coefficient, acute toxicity to Daphnia, toxicity to algae, and... coefficient, acute toxicity to Daphnia, toxicity to algae, and combined 28-day repeated-dose toxicity with...

  14. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... repeated dose study, shall be terminated at 7 days, or after at least 90 percent of the radioactivity has... percent of the radioactivity has been recovered in the excreta, whichever occurs first. (3) Types of...., Groups A, B, C, F), the concentration of radioactivity in blood and excreta including expired air...

  15. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... radioactivity following oral or dermal administration and total excretion following intravenous administration... repeated dosing study, shall be terminated at 7 days or after at least 90 percent of the radioactivity has... skin surface. Both the covering and the washing shall be assayed to recover residual radioactivity....

  16. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... radioactivity following oral or dermal administration and total excretion following intravenous administration... repeated dosing study, shall be terminated at 7 days or after at least 90 percent of the radioactivity has... skin surface. Both the covering and the washing shall be assayed to recover residual radioactivity....

  17. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... repeated dose study, shall be terminated at 7 days, or after at least 90 percent of the radioactivity has... percent of the radioactivity has been recovered in the excreta, whichever occurs first. (3) Types of...., Groups A, B, C, F), the concentration of radioactivity in blood and excreta including expired air...

  18. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... repeated dose study, shall be terminated at 7 days, or after at least 90 percent of the radioactivity has... percent of the radioactivity has been recovered in the excreta, whichever occurs first. (3) Types of...., Groups A, B, C, F), the concentration of radioactivity in blood and excreta including expired air...

  19. 40 CFR 795.228 - Oral/dermal pharmacokinetics.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... radioactivity following oral or dermal administration and total excretion following intravenous administration... repeated dosing study, shall be terminated at 7 days or after at least 90 percent of the radioactivity has... skin surface. Both the covering and the washing shall be assayed to recover residual radioactivity....

  20. 78 FR 58548 - Request for Information: The National Toxicology Program Requests Information on Use, Human...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-24

    ...) production, use, and consumption patterns in the United States; (3) genotoxicity, repeated dose toxicity... genotoxicity, subchronic toxicity, and mechanistic studies due to a lack of information on its potential..., the NTP found that published data on genotoxicity, carcinogenicity, and reproductive and...

  1. On-the-Road Driving Performance the Morning after Bedtime Use of Suvorexant 20 and 40 mg: A Study in Non-Elderly Healthy Volunteers

    PubMed Central

    Vermeeren, Annemiek; Sun, Hong; Vuurman, Eric F.P.M.; Jongen, Stefan; Van Leeuwen, Cees J.; Van Oers, Anita C.M.; Palcza, John; Li, Xiadong; Laethem, Tine; Heirman, Ingeborg; Bautmans, An; Troyer, Matthew D.; Wrishko, Rebecca; McCrea, Jacqueline

    2015-01-01

    Study Objective: To evaluate next-morning driving performance in adults younger than 65 years, after single and repeated doses of suvorexant 20 and 40 mg. Design: Double-blind, placebo-controlled, 4-period crossover study. Setting: Maastricht University, The Netherlands. Participants: 28 healthy volunteers (15 females), aged 23 to 64 years. Interventions: Suvorexant (20 and 40 mg) for 8 consecutive nights; zopiclone 7.5 mg nightly on day 1 and 8; placebo. Measurements: Performance on day 2 and 9 (9 h after dosing) using a one-hour standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo changes in SDLP > 2.4 cm were considered to reflect meaningful driving impairment. Results: Mean drug-placebo changes in SDLP following suvorexant 20 and 40 mg were 1.01 and 1.66 cm on day 2, and 0.48 and 1.31 cm on Day 9, respectively. The 90% CIs of these changes were all below 2.4 cm. Symmetry analysis showed that more subjects had SDLP changes > 2.4 cm than < −2.4 cm following suvorexant 20 and 40 mg on day 2, and following suvorexant 40 mg on day 9. Four female subjects requested that a total of 5 driving tests—all following suvorexant—stop prematurely due to self-reported somnolence. Conclusions: As assessed by mean changes in standard deviation of lateral position (SDLP), there was no clinically meaningful residual effect of suvorexant in doses of 20 and 40 mg on next-morning driving (9 h after bedtime dosing) in healthy subjects < 65 years old. There may be some individuals who experience next-day effects, as suggested by individual changes in SDLP and prematurely stopped tests. Clinical Trial Registration: clinicaltrials.gov NCT01311882. Citation: Vermeeren A, Sun H, Vuurman EF, Jongen S, Van Leeuwen CJ, Van Oers AC, Palcza J, Li X, Laethem T, Heirman I, Bautmans A, Troyer MD, Wrishko R, McCrea J. On-the-road driving performance the morning after bedtime use of suvorexant 20 and 40 mg: a study in non

  2. Diabetogenic effect of a series of tricyclic delta opioid agonists structurally related to cyproheptadine.

    PubMed

    Codd, Ellen E; Baker, Judith; Brandt, Michael R; Bryant, Stewart; Cai, Chaozhong; Carson, John R; Chevalier, Kristen M; Colburn, Raymond W; Coogan, Timothy P; Dax, Scott L; Decorte, Bart; Kemmerer, Michael; Legrand, Edmund K; Lenhard, James M; Leone, Angelique M; Lin, Ling; Mabus, John R; McDonnell, Mark E; McMillian, Michael K; McNally, James J; Stone, Dennis J; Wang, Charles Y; Zhang, Sui-Po; Flores, Christopher M

    2010-10-01

    The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic β-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic β-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.

  3. To study the effects of gamma irradiation on single donor apheresis platelet units by measurement of cellular counts, functional indicators and a panel of biochemical parameters, in order to assess pre-transfusion platelet quantity and quality during the shelf life of the product

    PubMed Central

    Mallhi, R.S.; Biswas, A.K.; Philip, J.; Chatterjee, T.

    2016-01-01

    Background The occurrence of transfusion associated graft versus host disease can be prevented by gamma irradiation of blood components. This study was undertaken to assess the effects of gamma irradiation on single donor platelet (SDP) concentrate units. Method SDPs were collected by a continuous flow apheresis technique (n = 400). The SDPs from each donor were divided into two parts, one gamma-irradiated with 25 Gy and the other used as a non-irradiated control. Swirling and morphological features, cellular counts, biochemical parameters including blood gas analysis, and platelet activation levels (CD62P: p-selectin) by flow cytometry were analyzed on Day 1 and on Day 5. Results Swirling and morphology were maintained in all products, in both the groups throughout the shelf life. No significant change was seen in both groups, on the first and fifth day, as far as pO2, pCO2, Na+, K+, HCO3− & Ca2+ were concerned. However, lactate increased and glucose decreased significantly in irradiated products over 5-day storage period. A small but significant decrease in pH and platelet count was found in the irradiated PCs after 5-day storage. The mean proportion of platelets expressing CD62P over 5-day storage increased significantly. Conclusion After an overall assessment of all our in vitro parameter results and observations, a few of which were significant, while most were not significant, we concluded that a well-preserved quality of gamma irradiated apheresis platelets is maintained throughout the entire 5-day shelf life of the platelet product, with minimal difference compared to non-irradiated platelets. PMID:26900218

  4. Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice

    PubMed Central

    Zheng, Jia; Goodyear, Laurie J.

    2016-01-01

    The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression. PMID:28058270

  5. Using Fresh Frozen Plasma for Acute Airway Angioedema to Prevent Intubation in the Emergency Department: A Retrospective Cohort Study

    PubMed Central

    Hagglund, Karen H.; Cigolle, Christine T.

    2016-01-01

    Background. Angioedema (AE) is a common condition which can be complicated by laryngeal edema, having up to 40% mortality. Although sporadic case reports attest to the benefits of fresh frozen plasma (FFP) in treating severe acute bouts of AE, little evidence-based support for this practice is available at present. Study Objectives. To compare the frequency, duration of intubation, and length of intensive care unit (ICU) stay in patients with acute airway AE, with and without the use of FFP. Methods. A retrospective cohort study was conducted, investigating adults admitted to large community hospital ICU with a diagnosis of AE during the years of 2007–2012. Altogether, 128 charts were reviewed for demographics, comorbidities, hospital courses, and outcomes. A total of 20 patients received FFP (108 did not). Results. Demographics and comorbidities did not differ by treatment group. However, nontreated controls did worse in terms of intubation frequency (60% versus 35%; p = 0.05) and ICU stay (3.5 days versus 1.5 days; p < 0.001). Group outcomes were otherwise similar. Conclusion. In an emergency department setting, the use of FFP should be considered in managing acute airway nonhereditary AE (refractory to steroid, antihistamine, and epinephrine). Larger prospective, better controlled studies are needed to devise appropriate treatment guidelines. PMID:26953061

  6. Filament-Prominence-Cme Magnetic Evolution Study

    NASA Astrophysics Data System (ADS)

    Bagala', L. G.; Mandrini, C. H.; Fernandez Borda, R.; de Pontieu, B.; Rovira, M. G.; Rank, G.

    1999-10-01

    The first results of the SOHO Joint Observation Program JOP 99 are outlined. JOP 99 involve several SOHO instruments (CDS, LASCO, MDI), together with TRACE, and two new ground-based instruments: HASTA (Hα Solar Telescope for Argentina) and MICA (Mirror Coronagraph for Argentina). The proposed program have a new motivation in taking advantage of the capabilities of the TRACE instrument, together with our experience in magnetic reconnection. The objective here is focused on the investigation of the conditions of the eruption of a prominence, often associated with the CME. JOP 99 is running at the moment that this abstract is submitted. It is a 5-days study of the filament/prominence, with 3-4 days observing the disk and 1-2 days observing the limb. While on disk, we will look for the eruption signatures in two ways: by studying the physical conditions in the filament and its surroundings (densities, temperature, abundances), and by looking at the magnetic topology changes. While at the limb, we will wait with luck for an eruption. If it does happen, LASCO and MICA observations will study if there exists an associated CME.

  7. Phase I study of the combination of two hypoxic cell radiosensitizers, Ro 03-8799 and SR-2508: toxicity and pharmacokinetics

    SciTech Connect

    Newman, H.F.; Bleehen, N.M.; Workman, P.

    1986-07-01

    The hypoxic cell radiosensitizer Ro 03-8799 produces acute central nervous system toxicity which limits repeated doses of the drug to 0.75 g/m/sup 2/, but peripheral neuropathy does not occur. SR-2508 causes no acute effects at doses greater than 3.0 g/m/sup 2/, but causes peripheral neuropathy at cumulative doses of 30 g/m/sup 2/. By combining maximum tolerated doses of each agent, it may be possible to increase efficacy, but not toxicity. Escalating single doses of Ro 03-8799 and SR-2508 were administered to 10 patients. The drugs were infused together in 50 ml of 0.9% saline over 10 min, beginning at 0.5 g/m/sup 2/ of each agent, and proceeding to a fixed dose of 0.75 g/m/sup 2/ Ro 03-8799 with 0.5, 1.0, 2.0, and 3.0 g/m/sup 2/ SR-2508. Four patients experienced the expected acute syndrome related to Ro 03-8799, but the incidence was not increased by escalating doses of SR-2508, and no peripheral neuropathy was seen. Plasma and urine pharmacokinetic studies showed that no drug interaction occurred. Six patients have been given a 9-dose regime over a 3 week period, using 0.75 g/m/sup 2/ Ro 03-8799 and escalating doses of 0.5, 1.0, and 1.5 g/m2 SR-2508. All exhibited the expected acute side effects related to Ro 03-8799, but with no increase at the higher doses of SR-2508. No other toxicity was seen. Plasma pharmacokinetics performed at the beginning and end of the schedule were similar. Biopsies were taken from six superficial tumors following combined radiosensitizer administration. Mean tumor concentrations over the 30 min following the end of infusion were 30 and 72 micrograms/g for Ro 03-8799 and SR-2508, respectively. These values would be expected to translate into an approximate single dose sensitizer enhancement ratio of 1.5 to 1.6, offering a significant gain over the enhancement possible with the drugs given alone.

  8. Phase I/II study of oncolytic herpes simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer metastatic to the liver.

    PubMed

    Geevarghese, Sunil K; Geller, David A; de Haan, Hans A; Hörer, Markus; Knoll, Anette E; Mescheder, Axel; Nemunaitis, John; Reid, Tony R; Sze, Daniel Y; Tanabe, Kenneth K; Tawfik, Hoda

    2010-09-01

    This multicenter phase I/II study evaluated the safety, pharmacokinetics, and antitumor effects of repeated doses of NV1020, a genetically engineered oncolytic herpes simplex virus, in patients with advanced metastatic colorectal cancer (mCRC). Patients with liver-dominant mCRC received four fixed NV1020 doses via weekly hepatic artery infusion, followed by two or more cycles of conventional chemotherapy. Phase I included cohorts receiving 3 × 10(6), 1 × 10(7), 3 × 10(7), and 1 × 10(8) plaque-forming units (PFU)/dose to determine the optimal biological dose (OBD) for phase II. Blind independent computed tomography scan review was based on RECIST (response evaluation criteria in solid tumors) to assess hepatic tumor response. Phase I and II enrolled 13 and 19 patients, respectively. Patients experienced transient mild-moderate febrile reactions after each NV1020 infusion. Grade 3/4 virus-related toxicity was limited to transient lymphopenia in two patients. NV1020 shedding was not detected. Simultaneous cytokine and grade 1 coagulation perturbations were dose-limiting at 1 × 10(8) PFU/dose, considered the OBD. All 22 OBD patients had previously received 5-fluorouracil; most had received oxaliplatin or irinotecan (50% had both), many with at least one targeted agent. After NV1020 administration, 50% showed stable disease. The best overall tumor control rate after chemotherapy was 68% (1 partial response, 14 stable disease); this did not correlate with baseline variables or chemotherapy. Median time to progression was 6.4 months (95% confidence interval: 2, 8.9); median overall survival was 11.8 months (95% confidence interval: 8.3, 20.7). One-year survival was 47.2%. We conclude that NV1020 stabilizes liver metastases with minimal toxicity in mCRC. It may resensitize metastases to salvage chemotherapy and extend overall survival. A randomized phase II/III trial now appears justified.

  9. Pharmacokinetics and Tolerability of Inhaled Umeclidinium and Vilanterol Alone and in Combination in Healthy Chinese Subjects: A Randomized, Open-Label, Crossover Trial

    PubMed Central

    Hu, Chaoying; Jia, Jingying; Dong, Kelly; Luo, Linda; Wu, Kai; Mehta, Rashmi; Peng, Jack; Ren, Yan; Gross, Annette; Yu, Hui

    2015-01-01

    Inhaled umeclidinium (UMEC) and the combination of inhaled UMEC with vilanterol (UMEC/VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. This was a randomized, open-label, three-period crossover, single- and repeat-dose study to assess the pharmacokinetics (PK), safety, and tolerability of inhaled UMEC/VI 62.5/25 μg (delivering 55/22 μg) and UMEC/VI 125/25 μg (delivering 113/22 μg) compared with their monotherapy components (UMEC 62.5 μg, UMEC 125 μg and, VI 25 μg [delivering 55, 113, and 22 μg, respectively]) in healthy Chinese subjects (n=20). UMEC and VI were rapidly absorbed following single and repeat dosing (time to maximum plasma concentration [tmax]: UMEC = 5 min; VI = 5 min). The median tlast was 2–4 h for UMEC and 1–2 h for VI following single doses of UMEC/VI and UMEC monotherapy (both doses). UMEC reached steady-state prior to Day 10; steady-state for VI could not be assessed. UMEC accumulation following repeat dosing was 11–34% based on Cmax and 19–59% based on area under the concentration-time curve from time zero to 2 h (AUC(0-2)). VI accumulation following repeat dosing was 25–66% based on Cmax and 17–43% based on AUC(0-2). The evidence was not sufficient to suggest that systemic exposure was substantially different between UMEC/VI combination therapy and the constituent monotherapies following single or repeat dosing. Following both single- and repeat-dose administration, the inter-subject coefficient of variation for all UMEC PK parameter estimates ranged from 12% to 165% for all treatments, indicating a wide range of variability in inhaled PK parameters. Twelve subjects experienced ≥1 adverse event (AE). Six subjects experienced ≥1 treatment-related AE; the most commonly reported treatment-related AE was chest discomfort (n=3 [15%]). No clinically important changes in vital signs or electrocardiogram parameters were reported. These data suggest that single- and repeat-dose

  10. Case study of psychophysiological diary: infradian rhythms.

    PubMed

    Slover, G P; Morris, R W; Stroebel, C F; Patel, M K

    1987-01-01

    A 4-year case study was made of a 42-year-old white woman as seen through the psychophysiological diary. There was an awakening diary and a bedtime diary composed of 125 variables. The data are divided into two series: series I containing a manic episode, and series II as a control. Spectral analysis shows infradian rhythms in hypoglycemia and fear (11 days) and time to fall asleep (5 days). Depressed feelings showed a circatrigintan (28-day) rhythm, which was not correlated with menses. Mania had an annual rhythm (spring) but no circatrigintan or less rhythm. The following correlations have a P value less than or equal to 0.01: mania was directly correlated with number of sleeping pills, time to really wake up, need for rest, moodiness, and helplessness, and indirectly with expectations, pressure at work, sense of time, and emotional state. Interestingly, awakening pulse is directly correlated with awakening temperature, number of sleeping pills, bedtime pulse, tiredness at bedtime, hypoglycemia, and fear. Bedtime pulse is directly correlated with awakening pulse and awakening temperature. Both pulse and temperature at bedtime are directly correlated with negative variables such as tiredness, moodiness, helplessness, and depression, and inversely correlated with positive variables such as happiness, loving, performance at work, and thinking efficiency. This study demonstrates a significant correlation between physiological variables.

  11. Toxicology and carcinogenesis studies of hexachloroethane (CAS No. 67-72-1) in F344/N rats (gavage studies). Technical report

    SciTech Connect

    Eastin, W.C.

    1989-08-01

    Toxicology and carcinogenesis studies were conducted by administering doses of 0, 10, or 20 mg/kg hexachloroethane in corn oil by gavage 5 days per week for 103 weeks to groups of 50 male rats. Groups of 50 female rats were administered 0, 80, or 160 mg/kg on the same schedule. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of hexachloroethane for male F344/N rats, based on the increased incidences of renal neoplasms. The marginally increased incidences of pheochromocytomas of the adrenal gland may have been related to hexachloroethane administration to male rats. There was no evidence of carcinogenic activity of hexachloroethane for female F344/N rats administered 80 or 160 mg/kg by gavage for 103 weeks.

  12. Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord.

    PubMed

    Shi, L; Tang, G P; Gao, S J; Ma, Y X; Liu, B H; Li, Y; Zeng, J M; Ng, Y K; Leong, K W; Wang, S

    2003-07-01

    Gene delivery into the spinal cord provides a potential approach to the treatment of spinal cord traumatic injury, amyotrophic lateral sclerosis, and spinal muscular atrophy. These disorders progress over long periods of time, necessitating a stable expression of functional genes at therapeutic levels for months or years. We investigated in this study the feasibility of achieving prolonged transgene expression in the rat spinal cord through repeated intrathecal administration of plasmid DNA complexed with 25 kDa polyethylenimine (PEI) into the lumbar subarachnoid space. With a single injection, DNA/PEI complexes could provide transgene expression in the spinal cord 40-fold higher than naked plasmid DNA. The transgene expression at the initial level persisted for about 5 days, with a low-level expression being detectable for at least 8 weeks. When repeated dosing was tested, a 70% attenuation of gene expression was observed following reinjection at a 2-week interval. This attenuation was associated with apoptotic cell death and detected even using complexes containing a noncoding DNA that did not mediate any gene expression. When each component of the complexes, PEI polymer or naked DNA alone, were tested in the first dosing, no reduction was found. Using polyethylene glycol (PEG)-grafted PEI for DNA complexes, no attenuation of gene expression was detected after repeated intrathecal injections, even in those rats receiving three doses, administered 2 weeks apart. Lumbar puncture is a routine and relatively nontraumatic clinical procedure. Repeated administration of DNA complexed with PEG-grafted PEI through this less invasive route may prolong the time span of transgene expression when needed, providing a viable strategy for the gene therapy of spinal cord disorders.

  13. Novel Arylimidamides for Treatment of Visceral Leishmaniasis▿ †

    PubMed Central

    Wang, Michael Zhuo; Zhu, Xiaohua; Srivastava, Anuradha; Liu, Qiang; Sweat, J. Mark; Pandharkar, Trupti; Stephens, Chad E.; Riccio, Ed; Parman, Toufan; Munde, Manoj; Mandal, Swati; Madhubala, Rentala; Tidwell, Richard R.; Wilson, W. David; Boykin, David W.; Hall, James Edwin; Kyle, Dennis E.; Werbovetz, Karl A.

    2010-01-01

    Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC50], <1 μM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro and in vivo antileishmanial activities, pharmacokinetics, mutagenicities, and toxicities of two novel AIAs, DB745 and DB766. They were exceptionally active (IC50 ≤ 0.12 μM) against intracellular L. donovani, Leishmania amazonensis, and Leishmania major and did not exhibit mutagenicity in an Ames screen. DB745 and DB766, given orally, produced a dose-dependent inhibition of liver parasitemia in two efficacy models, L. donovani-infected mice and hamsters. Most notably, DB766 (100 mg/kg of body weight/day for 5 days) reduced liver parasitemia in mice and hamsters by 71% and 89%, respectively. Marked reduction of parasitemia in the spleen (79%) and bone marrow (92%) of hamsters was also observed. Furthermore, these compounds distributed to target tissues (liver and spleen) and had a moderate oral bioavailability (up to 25%), a large volume of distribution, and an elimination half-life ranging from 1 to 2 days in mice. In a repeat-dose toxicity study of mice, there was no indication of liver or kidney toxicity for DB766 from serum chemistries, although mild hepatic cell eosinophilia, hypertrophy, and fatty changes were noted. These results demonstrated that arylimidamides are a promising class of molecules that possess good antileishmanial activity and desirable pharmacokinetics and should be considered for further preclinical development as an oral treatment for VL. PMID:20368397

  14. In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone.

    PubMed

    Hershkovitz, Oren; Bar-Ilan, Ahuva; Guy, Rachel; Felikman, Yana; Moschcovich, Laura; Hwa, Vivian; Rosenfeld, Ron G; Fima, Eyal; Hart, Gili

    2016-02-01

    MOD-4023 is a novel long-acting version of human growth hormone (hGH), containing the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG). MOD-4023 is being developed as a treatment for adults and children with growth hormone deficiency (GHD), which would require fewer injections than currently available GH formulations and thus reduce patient discomfort and increase compliance. This study characterizes MOD-4023's binding affinities for the growth hormone receptor, as well as the pharmacokinetic and pharmacodynamics, toxicology, and safety profiles of repeated dosing of MOD-4023 in Sprague-Dawley rats and Rhesus monkeys. Although MOD-4023 exhibited reduced in vitro potency and lower affinity to the GH receptor than recombinant hGH (rhGH), administration of MOD-4023 every 5 days in rats and monkeys resulted in exposure comparable to daily rhGH, and the serum half-life of MOD-4023 was significantly longer. Repeated administration of MOD-4023 led to elevated levels of insulin-like growth factor 1 (IGF-1), and twice-weekly injections of MOD-4023 resulted in larger increase in weight gain with fewer injections and a lower accumulative hGH dose. Thus, the increased half-life of MOD-4023 in comparison to hGH may increase the frequency of protein-receptor interactions and compensate for its decreased in vitro potency. MOD-4023 was found to be well-tolerated in rats and monkeys, with minimal adverse events, suggesting an acceptable safety profile. These results provide a basis for the continued clinical development of MOD-4023 as a novel treatment of GHD in children and adults.

  15. The efficacy of three formulations of Lippia sidoides Cham. essential oil in the reduction of salivary Streptococcus mutans in children with caries: a randomized, double-blind, controlled study.

    PubMed

    Lobo, Patrícia Leal Dantas; Fonteles, Cristiane Sá Roriz; Marques, Lídia Audrey Rocha Valadas; Jamacaru, Francisco Vagnaldo Fechine; Fonseca, Said Gonçalves da Cruz; de Carvalho, Cibele Barreto Mano; de Moraes, Maria Elisabete Amaral

    2014-01-01

    Essential oils of many plants have been previously tested in the treatment of oral diseases and other infections. This study was a randomized, double-blind, in parallel with an active control study, which aimed to evaluate the efficacy of three formulations of the Lippia sidoides Cham. essential oil (LSO) in the reduction of salivary Streptococcus mutans in children with caries. 81 volunteers, aged 6-12 years, both genders, with caries, were recruited to participate in this study, and randomly assigned to either one of five different groups. Each group received topical treatment with either 1.4% LSO toothpaste, 1.4% LSO gel, 0.8% LSO mouthwash, 1% chlorhexidine gel, or 0.12% chlorhexidine mouthwash. A 5-ml volume of each gel was placed inside disposable trays, and applied for 1 min, every 24h, for 5 consecutive days. The mouthwash groups used 5-ml volume of a mouthwash inside disposable syringes. In the toothpaste group, children brushed their teeth for 1 min, once a day for 5 days. Saliva was collected before and after treatment. MS colonies were counted, isolated and confirmed through biochemical tests. Differences in MS levels measured in different days within the same treatment group was only verified with LSO toothpaste, chlorhexidine gel and chlorhexidine mouthwash. Comparison between groups of LSO mouthwash, toothpaste and gel showed that the toothpaste group expressed significantly lower MS levels than the mouthwash and gel groups at day-30. Chlorhexidine significantly reduced MS levels after 5 days of treatment, but these levels returned to baseline in other periods of the study. LSO toothpaste reduced MS levels after 5 days of treatment, and MS levels remained low and did not return to baseline during subsequent analysis. Hence, LSO toothpaste demonstrated the most long-lasting MS reduction in saliva, whereas other LSO formulations did not effectively reduce MS levels in children with dental caries.

  16. Distribution of (/sup 14/C)acrylamide in male and pregnant Swiss-Webster mice studied by whole-body autoradiography

    SciTech Connect

    Marlowe, C.; Clark, M.J.; Mast, R.W.; Friedman, M.A.; Waddell, W.J.

    1986-12-01

    Male and 13.5- and 17.5-day pregnant Swiss-Webster mice were administered 120 mg/kg (2,3-14C)acrylamide orally. The male mice were frozen 0.33, 1, 3, 9, 24, 72, and 216 hr later, and the pregnant mice at each gestational period were frozen at 3 and 24 hr. Whole-body autoradiographs from the male mice at early time intervals revealed accumulation of radioactivity in the contents of the gastrointestinal tract, liver, pancreas, testis, brain and gallbladder, and epithelia of oral cavity, esophagus, and bronchi. The distribution appears to be similar in the male and pregnant mice. Absorption from the stomach was virtually complete by 3 hr; renal and hepatic elimination was essentially complete at 24 hr. Radioactivity in the male reproductive tract appeared in the parenchyma of the testis at 1 hr, moved to the seminiferous tubules and head of the epididymis at 9 hr, and by 9 days remained only in the tail of the epididymis and the crypts of the epithelium of the glans penis. This movement parallels that of spermatids. The 13.5-day fetuses were uniformly labeled except for a slightly increased uptake in fetal brain. The distribution of radioactivity in the 17.5-day fetal tissues resembled that in maternal tissues; the remarkable exception was an intense accumulation in fetal skin. This study indicates that acrylamide is efficiently absorbed from the stomach and eliminated by the liver, kidney, and possibly the pancreas. A previously unrecognized affinity of acrylamide or a metabolic product was demonstrated for fetal skin in late gestation and for adult epithelia of oral cavity, esophagus, forestomach, and bronchi. Also, acrylamide or a metabolite appears to bind to spermatids at a specific stage near maturation.

  17. Caloric test and video-head-impulse: a study of vertigo/dizziness patients in a community hospital.

    PubMed

    Mahringer, Andrea; Rambold, Holger A

    2014-03-01

    The head-impulse test (HIT) is an important test for examining unilateral vestibular hypofunction. The new video-head-impulse test (vHIT) is more sensitive and specific than the clinical bedside-head-impulse test (bHIT). Alternatively, one can test for vestibular hypofunction with the caloric irrigation test. Various studies showed that both tests may not always identify vestibular hypofunction; instead, the results of the tests might be contradictory. To evaluate the diagnostic value of these tests, we routinely measured patients exhibiting vertigo or dizziness at our community hospital with bithermal caloric irrigation, the bHIT and the vHIT. Only those patients (n = 172) with a pathological caloric irrigation test of more than 25 % unilateral weakness in the Jongkee's formula were included. Out of these patients, 41 % had a pathologic vHIT. Among the subgroup with acute symptoms (symptom onset within 5 days), 63 % had a pathological video-head-impulse, whereas only 33 % of the non-acute group (symptom onset more than 5 days) tested pathological. A pathological HIT depended on the disease stage, the amount of unilateral weakness in caloric examination and on the test itself.

  18. [Epizootiologic studies of trichophytosis in cattle].

    PubMed

    Kamyszek, F

    1975-01-01

    Investigations were carried out during the years 1964 to 1973. The investigated material included 34 134 heads of cattle in 227 industrial farms, and 80 per cent of them were young animals, from 5 days to 22 months old. The aim of the study was to observe the intensity of skin mycosis in cattle in the Poznań Province, to determine the pathogenic factor causing the disease in individual years, and to search for a possible relation between the occurrence of this disease and the presence of ectoparasites. The clinical observations on cattle were continued for 9 years, 1932 samples of scrapings were taken from skin with mycotic changes and investigated from the points of view of mycology and parasitology. Basing on the observations and analyses performed, it was found that trichophytosis occurred during the whole year, but was more intensive in autumn and winter and in the wet period of summer. Young animals were more frequently affected with this disease. In individual groups of animals, in 10.9 to 21.1% of cases, trichophytosis occurred together with invasion of ectoparasites (lice, mallophagans, itch mites).

  19. In vivo studies of polyacrylate nanoparticle emulsions for topical and systemic applications.

    PubMed

    Greenhalgh, Kerriann; Turos, Edward

    2009-03-01

    We have recently reported on a new nanomedicine containing antibiotic-conjugated polyacrylate nanoparticles, which has shown activity against methicillin-resistant Staphylococcus aureus (MRSA) in vitro and no cytotoxicity toward human dermal cells. The water-based nanoparticle emulsion is capable of solubilizing lipophilic antibiotics for systemic administration, and the nanoparticle drug delivery vehicle has shown protective properties for antibiotics from hydrolytic cleavage by bacterial penicillinases, thus rejuvenating the drug's activity against resistant microbes such as MRSA. Here we report the first in vivo study of this penicillin-conjugated nanoparticle emulsion in determining toxicological responses initiated upon systemic and topical application in a murine model. Favorable results were observed in vivo upon both routes of administration and, when topically applied to a dermal abrasion model, the emulsion enhanced wound healing by an average of 3 to 5 days. This study suggests that polyacrylate nanoparticle-containing emulsions may afford promising opportunities for treating both skin and systemic infections.

  20. Effects of myrrh on the strength of suture materials: an in vitro study.

    PubMed

    Alshehri, Mohammed A; Baskaradoss, Jagan Kumar; Geevarghese, Amrita; Ramakrishnaiah, Ravikumar; Tatakis, Dimitris N

    2015-01-01

    The present in vitro study sought to determine the effects of myrrh-containing solutions on common suture materials used in periodontal surgery. Three commonly used suture materials (silk, polyglactin 910, polytetrafluoroethylene) were immersed in four thermostatically controlled experimental media to simulate daily oral rinsing activity, namely -artificial saliva, normal saline solution with 0.2% Commiphora myrrh, full-concentration (100%) Commiphora myrrh oil, and a myrrh-containing commercial mouthwash. Tensile strength was measured at the end of each day using an Instron tensile testing machine. Silk sutures were susceptible to tensile strength loss when exposed to 0.2% myrrh solution once daily for 5 days. Myrrh-containing commercial mouthwash had no effect on tensile strength, but all three suture materials lost tensile strength when exposed to 100% myrrh oil. For patients that routinely use myrrh mouthwashes postoperatively, findings of this study suggested that silk sutures might not be the optimal material choice.

  1. Ketamine does not inhibit interleukin-6 synthesis in hepatic resections requiring a temporary porto-arterial occlusion (Pringle manoeuvre): a controlled, prospective, randomized, double-blinded study

    PubMed Central

    Bonofiglio, Francisco Carlos; Molmenti, Ernesto P; de Santibañes, Eduardo

    2011-01-01

    Introduction Previous studies have shown that interleukin-6 (IL-6) levels correlated with mortality in critically ill patients. Goal To determine the effect of ketamine on IL-6 levels in liver resections patients with a temporary porto-arterial occlusion (Pringle manoeuvre). Materials and methods Controlled, prospective, randomized, double-blinded study. One group (n = 21) received ketamine whereas the other group (n = 17) received placebo. IL-6 levels were obtained at baseline, 4, 12, 24 h, 3 and 5 days. Results There were no significant differences in IL-6 levels between the groups (basal P = 089, 4 h P = 0.83, 12 h P = 0.39, 24 h, P = 0.55, 3 days P = 0.80 and 5 days P = 0.45). Both groups had elevated IL-6 levels that became almost undetectable by day 5. There was no major morbidity and no mortality in either group. Conclusions Ketamine does not seem to have an effect on plasma levels of IL-6. This could be interpreted as a potential finding associated with outcome as we did not encounter any deaths or major complications. Further studies will likely be needed to determine the range of IL-6 levels associated with survival and mortality, and whether it could be a predictor of survival. PMID:21929671

  2. Nosocomial Rotavirus Gastroenteritis in pediatric patients: a multi-center prospective cohort study

    PubMed Central

    2010-01-01

    Background Few data are available on the incidence of nosocomial Rotavirus infections (NRVI) in pediatric hospitals and on their economic impact. The goals of this study were: to evaluate the incidence of NRVI in various Italian pediatric wards during the course of two peak RV seasons; to investigate possible risk factors for NRVI; to estimate the costs caused by NRVI. Methods prospective cohort study. Population: all the children under 30 months of age who were admitted without any symptom or diagnosis of gastroenteritis in the pediatric hospitals of Florence, Naples, Brescia and Ancona, Italy, during the winter-spring periods 2006-2007 and 2007-2008. Serial RV rapid tests and clinical monitoring were carried out on the cohort. Telephone interviews were performed from 3 to 5 days after discharge. Results 520 out of 608 children completed the study (85.6%). The overall incidence of NRVI was 5.3% (CI95% 3.6-7.5), (7.9 per 1,000 days of hospital stay, CI 95% 5.3-11.3). The average duration of hospital stay was significantly longer for children who had NRVI (8.1 days, SD 5.4) than for non-infected children (6.4 days, SD 5.8, difference 1.7 days, p = 0.004). The risk of contracting NRVI increased significantly if the child stayed in hospital more than 5 days, RR = 2.8 (CI95% 1.3-6), p = 0.006. In Italy the costs caused by NRVI can be estimated at 8,019,155.44 Euro per year. 2.7% of the children hospitalized with no gastroenteritis symptoms tested positive for RV. Conclusions Our study showed a relevant incidence of NRVI, which can increase the length of the children's stay in hospital. Limiting the number of nosocomial RV infections is important to improve patients' safety as well as to avoid additional health costs. PMID:20696065

  3. Hematology and immunology studies

    NASA Technical Reports Server (NTRS)

    Kimzey, S. L.

    1977-01-01

    A coordinated series of experiments were conducted to evaluate immunologic and hemotologic system responses of Skylab crewmen to prolonged space flights. A reduced PHA responsiveness was observed on recovery, together with a reduced number of T-cells, with both values returning to normal 3 to 5 days postflight. Subnormal red cell count, hemoglobin concentration, and hematocrit values also returned gradually to preflight limits. Most pronounced changes were found in the shape of red blood cells during extended space missions with a rapid reversal of these changes upon reentry into a normal gravitational environment.

  4. A STUDY OF FISCHER 344 RATS EXPOSED TO SILICA DUST AT CONCENTRATIONS OF 0, 2, 10 OR 20 MG/M3, THEN MAINTAINED FOR SIX MONTHS PRIOR TO ASSESSMENT.

    SciTech Connect

    KUTZMAN,R.S.

    1984-11-01

    The major objective of this study was to relate the results of a series of functional tests to the compositional and structural alterations in the rat lung induced by subchronic exposure to silica dust. To induce a fibrotic lesion, Fischer-344 rats were exposed to either 0, 2, 10, or 20 mg Si0{sub 2}/m{sup 3} for 6 hours/day, 5 days/week for six months and then maintained in an animal room, equipped with a laminar flow unit, for six months prior to assessment of the end points.

  5. Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

    PubMed Central

    Meininger, Vincent; Pradat, Pierre-François; Corse, Andrea; Al-Sarraj, Safa; Rix Brooks, Benjamin; Caress, James B.; Cudkowicz, Merit; Kolb, Stephen J.; Lange, Dale; Leigh, P. Nigel; Meyer, Thomas; Milleri, Stefano; Morrison, Karen E.; Orrell, Richard W.; Peters, Gary; Rothstein, Jeffrey D.; Shefner, Jeremy; Lavrov, Arseniy; Williams, Nicola; Overend, Phil; Price, Jeffrey; Bates, Stewart; Bullman, Jonathan; Krull, David; Berges, Alienor; Abila, Bams; Meno-Tetang, Guy; Wurthner, Jens

    2014-01-01

    The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co

  6. Synchrotron studies of narrow band materials. Progress report, July 1, 1991--June 30, 1992

    SciTech Connect

    Not Available

    1992-07-01

    Since last year, we have had three 3-week blocks of beamtime, in April and November 1991 and February 1992, on the Ames/Montana beamline at the Wisconsin Synchrotron Radiation Center (SRC). These runs continued our program on high temperature superconductors, heavy Fermion and related uranium and rare earth materials, and started some work on transition metal oxides. We have also had beamtime at the Brookhaven NSLS, 5 days of beamtime on the Dragon monochromator, beamline U4B, studying resonant photoemission of transition metal oxides using photon energies around the transition metal 2p edges. Data from past runs has been analyzed, and in some cases combined with photoemission and bremsstrahlung isochromat spectroscopy (BIS) data taken in the home U-M lab. 1 fig.

  7. Transdermal clonidine in the prophylaxis of episodic cluster headache: an open study.

    PubMed

    Leone, M; Attanasio, A; Grazzi, L; Libro, G; D'Amico, D; Moschiano, F; Bussone, G

    1997-10-01

    Transdermal clonidine has recently been reported to be efficacious in the prophylaxis of cluster headache. A 2-week course of transdermal clonidine (5 mg the first week, 7.5 mg the second week) preceded by a 5-day run-in period, was administered to 16 patients with episodic cluster headache in an active cluster period. In 5 patients, the painful attacks disappeared after the seventh day of treatment. For the group as a whole, no significant variations in headache frequency, pain intensity, or attack duration were observed between the run-in period and the first and second weeks of treatment (ANOVA). Further studies are necessary to clarify the effectiveness of transdermal clonidine in the prophylaxis of episodic cluster headache.

  8. Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study

    PubMed Central

    Silva, Daniella M.; Franciosi, Aline I.; Pezzini, Paula C.F.; Guérios, Simone D.

    2015-01-01

    Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m2, SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m2 (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction. PMID:26246628

  9. Subcutaneous administration of paclitaxel in dogs with cancer: A preliminary study.

    PubMed

    Silva, Daniella M; Franciosi, Aline I; Pezzini, Paula C F; Guérios, Simone D

    2015-08-01

    Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m(2), SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m(2) (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction.

  10. Study of the system of middle atmosphere-ionosphere using remote-sensing data

    NASA Technical Reports Server (NTRS)

    Hass, H.; Ebel, A.; Hartmann, G. K.; Leitinger, R.

    1984-01-01

    In the present investigation, the methods of statistical spectral analysis are employed for a study of the quasi-periodic changes of state parameters of the middle atmosphere and the ionosphere, taking into account oscillations with periods of several days. The considered oscillations are typical for planetary waves. The theory and empirical findings regarding transient planetary waves are utilized as a basis for the concepts employed in the data analysis and for the interpretation of the results. The results of the investigation show a presence of coherent variations in the time series of radiation density measurements and other state parameters for the middle atmosphere and the ionosphere. The existence of presumably dynamic coupling processes can be recognized in oscillations with periods of about 16 or 5 days.

  11. Study of the system of middle atmosphere-ionosphere using remote-sensing data

    SciTech Connect

    Hass, H.; Ebel, A.; Hartmann, G.K.; Leitinger, R.

    1984-02-01

    In the present investigation, the methods of statistical spectral analysis are employed for a study of the quasi-periodic changes of state parameters of the middle atmosphere and the ionosphere, taking into account oscillations with periods of several days. The considered oscillations are typical for planetary waves. The theory and empirical findings regarding transient planetary waves are utilized as a basis for the concepts employed in the data analysis and for the interpretation of the results. The results of the investigation show a presence of coherent variations in the time series of radiation density measurements and other state parameters for the middle atmosphere and the ionosphere. The existence of presumably dynamic coupling processes can be recognized in oscillations with periods of about 16 or 5 days. G.R. (IAA)

  12. Study of the effects of electroacupuncture in a rodent model of cerebral ischaemia.

    PubMed

    Domenici, Rosaria Maria; Mingfu, Luo; Tebano, Maria Teresa; Reggio, Rosaria; Chiarotti, Flavia; Petti, Filomena; Liguori, Aldo; Popoli, Patrizia

    2003-01-01

    The effects of electroacupuncture (EA) has been studied in a model of global cerebral ischaemia performed in gerbils through the bilateral carotid artery occlusion (BCAO). Animals, under isofluorane anaesthesia, underwent 5 min of BCAO and were killed after 7 days. The effects of EA were evaluated both on functional (with electrophysiological recordings of synaptic potentials in hippocampal slices) and morphological parameters (by counting the number of survived neurons in CA1 area of the hippocampus). The results demonstrated that the treatment of animals with EA (5 min before, during and 20 min after BCAO and 30 min per day in the following 5 days) did not modify either the ischaemia-induced reduction of synaptic potentials amplitude, either ischaemia-induced neuronal loss in the hippocampus. We conclude that, at least in this animal model of cerebral ischaemia, EA does not exert a neuroprotective effect.

  13. Who Studies Women's Studies?

    ERIC Educational Resources Information Center

    Price, Marion; Owen, Mairead

    1998-01-01

    Studied a cohort (originally 44) of students who entered a British university to study women's studies in 1994. The strong emphases on the salience of the students' choice and the experiential importance of identity as a concept were striking. Theoretical difficulties in theorizing identity are explored. (SLD)

  14. A part-randomized study of intravenous oseltamivir in adolescents and adults.

    PubMed

    Várkonyi, I; Chappey, C; Giraudon, M; Burleigh, L

    2015-06-01

    Seriously ill patients with influenza may be unable to take oral medication. The safety of intravenous oseltamivir was evaluated in adults and adolescents. This prospective, part-randomized study enrolled hospitalized patients aged ≥13 years with clinical or laboratory-confirmed influenza, who started study medication within 144 h of illness onset. Patients with normal renal function received oseltamivir 100 or 200 mg every 12 h for 5 days by slow intravenous infusion. Patients with renal impairment received lower doses, appropriate to the degree of impairment. Blood samples were taken for pharmacokinetics, and nasal swabs were taken to monitor viral shedding and resistance [reverse transcription polymerase chain reaction (RT-PCR) and culture]. Adverse events (AEs) were monitored for 30 days from treatment initiation. Of the 118 patients enrolled, 103 had normal renal function. On day 1, 64 patients had laboratory-confirmed influenza. Ninety-four (80 %) patients completed 5 days of oseltamivir treatment (32 intravenous only). Sixty-eight and 13 patients reported on-treatment AEs and serious AEs (SAEs), respectively (62 and nine during intravenous dosing, respectively). For 33 and six patients, these AEs and SAEs were considered treatment-related (31 and five during intravenous dosing, respectively); 11 patients had AEs causing treatment withdrawal. Five patients died. Adequate systemic exposure to oseltamivir carboxylate (OC) was achieved at the intravenous doses tested. Oseltamivir-resistant viruses (H275Y) were detected in two patients. In seriously ill, hospitalized patients with/without renal impairment, intravenous oseltamivir was not associated with adverse safety findings at the dosages tested and achieved systemic OC exposures at least as high as the approved oral dose.

  15. Developing complex interventions: lessons learned from a pilot study examining strategy training in acute stroke rehabilitation

    PubMed Central

    Skidmore, Elizabeth R.; Dawson, Deirdre R.; Whyte, Ellen M.; Butters, Meryl A.; Dew, Mary Amanda; Grattan, Emily S.; Becker, James T.; Holm, Margo B.

    2013-01-01

    Objective To examine the feasibility of a strategy training clinical trial in a small group of adults with stroke-related cognitive impairments in inpatient rehabilitation, and to explore the impact of strategy training on disability. Design Non-randomized two-group intervention pilot study Setting Two inpatient rehabilitation units within an academic health center Participants Individuals with a primary diagnosis of acute stroke, who were admitted to inpatient rehabilitation and demonstrated cognitive impairments were included. Individuals with severe aphasia; dementia; major depressive disorder, bipolar, or psychotic disorder; recent drug or alcohol abuse; and anticipated length of stay less than 5 days were excluded. Intervention Participants received strategy training or an attention control session in addition to usual rehabilitation care. Sessions in both groups were 30–40 minutes daily, 5 days per week, for the duration of inpatient rehabilitation. Main Outcome Measures We assessed feasibility through participants’ recruitment and retention; research intervention session number and duration; participants’ comprehension and engagement; intervention fidelity; and participants’ satisfaction. We assessed disability at study admission, inpatient rehabilitation discharge, 3 and 6 months using the Functional Independence Measure. Results Participants in both groups (5 per group) received the assigned intervention (>92% planned sessions; >94% fidelity) and completed follow-up testing. Strategy training participants in this small sample demonstrated significantly less disability at 6 months [M(SE)=117 (3)] than attention control participants [M(SE)=96 (14); t8=7.87, p=.02]. Conclusions It is feasible and acceptable to administer both intervention protocols as an adjunct to acute inpatient rehabilitation, and strategy training shows promise for reducing disability. PMID:24113727

  16. Effect of post space preparation on the sealing ability of mineral trioxide aggregate and Gutta-percha: A bacterial leakage study

    PubMed Central

    Metgud, Sandeep S; Shah, Harsh H; Hiremath, Hemalatha T; Agarwal, Deepali; Reddy, Kartik

    2015-01-01

    Aim: The purpose of this study was to evaluate the effect of post space preparation on the sealing ability of teeth obturated with mineral trioxide aggregate (MTA) and Gutta-percha. Materials and Methods: Fifty intact human mandibular premolars, after decoronation and biomechanical preparation, were randomly divided into three experimental groups. In Group A (n = 10), the canals were obturated with Gutta-percha using cold lateral compaction technique, followed by immediate post space preparation. In Group B (n = 10), the canals were obturated with 8 mm of MTA and in Group C (n = 10), sectional obturation with 4 mm of MTA was done, followed by delayed post space preparation. All specimens were subjected to bacterial leakage analysis, and the occurrence of turbidity was checked. Results: All specimens in the lateral compaction group leaked. The mean number of days at which leakage was observed in Groups A, B and C were 18.5 days, 93.6 days and 95.5 days. Conclusions: MTA can be considered as an alternative to Gutta-percha as an apical third restorative material for teeth indicated for post and core, as it demonstrates better-sealing ability compared with Gutta-percha. Further, the removal of set MTA for post space preparation does not disrupt the integrity of the remaining apical MTA. PMID:26180414

  17. Synthetic vitreous fibers--inhalation studies.

    PubMed

    McConnell, E E

    1994-12-01

    Synthetic vitreous fibers (SVFs), often referred to as "man-made vitreous fibers," are a class of materials that have their major uses for insulation against heat and sound. The original fibers are produced by melting various types of rock, clay, etc. and then blowing or extruding them into fibers of particular properties. During production and use small fractions of airborne fibers can be generated. Because of this a series of state-of-the-art inhalation studies was initiated to study the possible health hazards presented by the four major types of vitreous materials [two types of insulation glass wool, rock wool, slag wool, and four types of refractory ceramic fibers (RCF)] found in the workplace or to which the general public may be exposed. Rats and hamsters (30 mg/m3 kaolin-based RCF only) were exposed by nose-only inhalation to 3, 16, or 30 mg/m3 for 6 hr/day, 5 days/week, for 18 (hamsters) or 24 (rats) months and were held for lifetime observation (until approximately 20% survival) to study the chronic toxicity and potential carcinogenic activity of these classes of SVFs. Chrysotile or crocidolite asbestos served as positive controls. All of the fibers stimulated an inflammatory response characterized by an increase in the number of pulmonary macrophages at the level of the terminal bronchioles and proximal alveoli. RCF produced interstitial fibrosis in the walls of the proximal alveoli as early as 3 months and rock wool by 12 months. The only fiber which showed carcinogenic activity was RCF which produced a dose-related increase in both primary lung neoplasms (rats only) and mesotheliomas (rats and hamsters).

  18. Assessing the Influence of a Fitbit Physical Activity Monitor on the Exercise Practices of Emergency Medicine Residents: A Pilot Study

    PubMed Central

    2017-01-01

    Background Targeted interventions have improved physical activity and wellness of medical residents. However, no exercise interventions have focused on emergency medicine residents. Objective This study aimed to measure the effectiveness of a wearable device for tracking physical activity on the exercise habits and wellness of this population, while also measuring barriers to adoption and continued use. Methods This pre-post cohort study enrolled 30 emergency medicine residents. Study duration was 6 months. Statistical comparisons were conducted for the primary end point and secondary exercise end points with nonparametric tests. Descriptive statistics were provided for subjective responses. Results The physical activity tracker did not increase the overall self-reported median number of days of physical activity per week within this population: baseline 2.5 days (interquartile range, IQR, 1.9) versus 2.8 days (IQR 1.5) at 1 month (P=.36). There was a significant increase in physical activity from baseline to 1 month among residents with median weekly physical activity level below that recommended by the Centers for Disease Control and Prevention at study start, that is, 1.5 days (IQR 0.9) versus 2.4 days (IQR 1.2; P=.04), to 2.0 days (IQR 2.0; P=.04) at 6 months. More than half (60%, 18/30) of participants reported a benefit to their overall wellness, and 53% (16/30) reported a benefit to their physical activity. Overall continued use of the device was 67% (20/30) at 1 month and 33% (10/30) at 6 months. Conclusions The wearable physical activity tracker did not change the overall physical activity levels among this population of emergency medicine residents. However, there was an improvement in physical activity among the residents with the lowest preintervention physical activity. Subjective improvements in overall wellness and physical activity were noted among the entire study population. PMID:28143805

  19. Effects of Acute Oral 5-aminotetrazole (5-AT) Exposure to Rats (Rattus norvegicus)

    DTIC Science & Technology

    2015-02-12

    Micronucleus Assay (MNA) Male rats from the 5-AT study (three highest dose groups and the vehicle control) were tested for DNA damage in their peripheral...Dose Test (Sub-acute Study) - Sperm Collection and Analysis 09/25/2013 10/07/2013 14-Day Repeated Dose Test (Sub-acute Study) - Micronucleus Assay...2015 Prepared by: Valerie H Adams, Ph.D. Approved for public release; distribution unlimited. Specialty: 500C Toxicity Test Toxicity Report No. S

  20. The impact of bismuth addition to sequential treatment on Helicobacter pylori eradication: A pilot study.

    PubMed

    Basyigit, Sebahat; Kefeli, Ayse; Sapmaz, Ferdane; Yeniova, Abdullah Ozgür; Asilturk, Zeliha; Hokkaomeroglu, Murat; Uzman, Metin; Nazligul, Yasar

    2015-10-25

    The success of the current anti-Helicobacter pylori (H. pylori) treatment protocols is reported to decrease by years, and research is needed to strengthen the H. pylori eradication treatment. Sequential treatment (ST), one of the treatment modalities for H. pylori eradication, includes amoxicillin 1 gr b.i.d and proton pump inhibitor b.i.d for first 5 days and then includes clarithromycin 500 mg b.i.d, metronidazole 500 mg b.i.d and a proton pump inhibitor b.i.d for remaining 5 days. In this study, we investigated efficacy and tolerability of bismuth addition in to ST. We included patients that underwent upper gastrointestinal endoscopy in which H. pylori infection was diagnosed by histological examination of antral and corporal gastric mucosa biopsy. Participants were randomly administered ST or bismuth containing ST (BST) protocols for the first-line H. pylori eradication therapy. Participants have been tested by urea breath test for eradication success 6 weeks after the completion of treatment. One hundred and fifty patients (93 female, 57 male) were enrolled. There were no significant differences in eradication rates for both intention to treat population (70.2%, 95% confidence interval [CI]: 66.3-74.1% vs. 71.8%, 95% CI: 61.8-81.7%, for ST and BST, respectively, p>0.05) and per protocol population (74.6%, 95% CI: 63.2-85.8% vs. 73.7%, 95% CI: 63.9-83.5% for ST and BST, respectively, p>0.05). Despite the undeniable effect of bismuth, there may be several possible reasons of unsatisfactory eradication success. Drug administration time, coadministration of other drugs, possible H. pylori resistance to bismuth may affect the eradication success. The addition of bismuth subcitrate to ST regimen does not provide significant increase in eradication rates.

  1. The Impact of Early Tracheostomy in Neurotrauma Patients: A Retrospective Study

    PubMed Central

    Zirpe, Kapil G.; Tambe, Deepali Vishnu; Deshmukh, Abhijit M.; Gurav, Sushma K.

    2017-01-01

    Background: Although majority of neurotrauma patients require long term ventilatory support but the timing of tracheostomy in such patients is controversial. Method: This retrospective study was conducted at a Tertiary Care Hospital, Pune, India. Patients >18 years of age, who underwent percutaneous tracheostomy (PCT) from June 2010 to November 2014 at neurotrauma unit (NTU) of hospital, were included. Patients were divided in two groups according to the timing of tracheostomy, early tracheostomy (ET) group (≤5 days; N=100) and late tracheostomy (LT) group (>5 days; N=64). The nonparametric Mann-Whitney test, and Chi-square tests were used to compare these groups. Result: There were no significant differences between the groups in terms of age, sex, APACHE II and GCS Score. Patients in the ET group had a significantly shorter stay in the NTU compared to patients in the LT group (mean, 18 vs. 21.2 days, p=0.005), fewer mechanical ventilation days (mean, 8.1 vs. 11.7 days, P=0.000) and shorter length of stay in hospital (mean, 28.8 vs. 34.37 days, P=0.019). There was no difference between ET and LT groups in post PCT ventilator free days (mean, 8.2 vs. 9.4 days; P=0.094). Mortality rates in ET vs. LT groups were also comparable (35% vs. 29.7%; P=0.480). Conclusion: Results suggest that ET in neurotrauma patients might be associated with shorter length of stay in NTU and hospital, and shorter duration of mechanical ventilation however there was no mortality difference. PMID:28197044

  2. Preliminary study on the effect of oral care on recovery from surgery in elderly patients.

    PubMed

    Sato, M; Yoshihara, A; Miyazaki, H

    2006-11-01

    This study aimed to clarify the effectiveness of post-operative oral care, including tooth brushing, denture cleaning and tongue cleaning, after digestive tract surgery. Subjects included 30 elderly patients aged 60-98 years (74.9 +/- 7.8 years) who underwent digestive tract surgery. Subjects were randomly divided into an intervention group and a control group. In the intervention group, the following oral care was provided daily over a 5-min period in the morning starting at baseline (day of surgery) and continued for 5 days: gargling with povidone iodine, tooth brushing, denture cleaning using a special brush and tongue cleaning using a tongue brush. In the control group, the subjects only gargled with povidone iodine. We compared the following variables between the two groups at baseline and 5 days later: the sensation of dry mouth, intra-oral gas concentration, pulmonary sounds, body temperature and bacterial flora. The number of patients with abnormal pulmonary sounds (dry or moist rales) increased from 1 to 2 in the intervention group and from 0 to 4 in the control group (P < 0.05). The average number of bacterial species per subject for the control group was 3.64 +/- 1.34 pre-operatively and 3.50 +/- 1.74 post-operatively, whereas that for the intervention group was 3.08 +/- 0.95 pre-operatively and 2.62 +/- 0.65 post-operatively. In the intervention group, there was a significant decrease in the number of bacterial species (P < 0.05). These findings indicate that post-operative oral care in elderly patients undergoing digestive tract surgery lowers the number of bacterial species found in the oral cavity. This effect, in turn, might improve respiratory function.

  3. Predicting Negative Emotions Based on Mobile Phone Usage Patterns: An Exploratory Study

    PubMed Central

    Yang, Pei-Ching; Chang, Chia-Chi; Chiang, Jung-Hsien; Chen, Ying-Yeh

    2016-01-01

    Background Prompt recognition and intervention of negative emotions is crucial for patients with depression. Mobile phones and mobile apps are suitable technologies that can be used to recognize negative emotions and intervene if necessary. Objective Mobile phone usage patterns can be associated with concurrent emotional states. The objective of this study is to adapt machine-learning methods to analyze such patterns for the prediction of negative emotion. Methods We developed an Android-based app to capture emotional states and mobile phone usage patterns, which included call logs (and use of apps). Visual analog scales (VASs) were used to report negative emotions in dimensions of depression, anxiety, and stress. In the system-training phase, participants were requested to tag their emotions for 14 consecutive days. Five feature-selection methods were used to determine individual usage patterns and four machine-learning methods were tested. Finally, rank product scoring was used to select the best combination to construct the prediction model. In the system evaluation phase, participants were then requested to verify the predicted negative emotions for at least 5 days. Results Out of 40 enrolled healthy participants, we analyzed data from 28 participants, including 30% (9/28) women with a mean (SD) age of 29.2 (5.1) years with sufficient emotion tags. The combination of time slots of 2 hours, greedy forward selection, and Naïve Bayes method was chosen for the prediction model. We further validated the personalized models in 18 participants who performed at least 5 days of model evaluation. Overall, the predictive accuracy for negative emotions was 86.17%. Conclusion We developed a system capable of predicting negative emotions based on mobile phone usage patterns. This system has potential for ecological momentary intervention (EMI) for depressive disorders by automatically recognizing negative emotions and providing people with preventive treatments before it

  4. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Modified Dominant Lethal Study of Sulfur Mustard in Rats Final Report

    SciTech Connect

    Sasser, L. B.; Cushing, J. A.; Kalkwarf, D. R.; Buschbom, R. L.

    1989-05-01

    Occupational health standards have not been established for sulfur mustard (HD) [bis{2-chloroethyl)-sulfide) ' a strong alkylating agent with known mutagenic properties. Little, however, is known about the mutagenic activity of HD in mammalian species and data regarding the dominant lethal effects of HD are ambiguous. The purpose of this study was to determine the dominant lethal effect in male and female rats orally exposed to HD. The study was conducted in two phases; a female dominant lethal phase and a male dominant lethal phase. Sprague-Dawley rats of each sex were administered 0.08, 0.20, or 0.50 mg/kg HD in sesame oil 5 days/week for 10 weeks. For the female phase, treated or untreated males were mated with treated females and their fetuses were evaluated at approximately 14 days after copulation. For the male dominant lethal phase, treated males cohabited with untreated femal (during 5 days of each week for 10 weeks) and females were sacrificed for fetal evaluation 14 days after the midweek of cohabitation during each of the 10 weeks. The appearance and behavior of the rats were unremarkable throughout the experiment and there were no treatment-related deaths. Growth rates were reduced in both female and male rats treated with 0.50 mg/kg HD. Indicators of reproductive performance did not demonstrate significant female dominant lethal effects, although significant male dominant lethal effects were observed at 2 and 3 week post-exposure. These effects included increases of early fetal resorptions and preimplantation losses and decreases of total live embryo implants. These effects were most consistently observed at a dose of 0.50 mg/kg, but frequently occurred at the lower doses. Although no treatment-related effects on male reproductive organ weights or sperm motility were found, a significant increase in the percentage of abnormal sperm was detected in males exposed to 0. 50 mg/kg HD. The timing of these effects is consistent with an effect during the

  5. A Comprehensive Toxicological Safety Assessment of an Extract of Olea Europaea L. Leaves (Bonolive™).

    PubMed

    Clewell, Amy E; Béres, Erzsébet; Vértesi, Adél; Glávits, Róbert; Hirka, Gábor; Endres, John R; Murbach, Timothy S; Szakonyiné, Ilona Pasics

    2016-01-01

    A battery of toxicological studies was conducted to investigate the genotoxicity and repeated-dose oral toxicity of Bonolive™, a proprietary water-soluble extract of the leaves of the olive tree (Olea europaea L.), in accordance with internationally accepted protocols. There was no evidence of mutagenicity in a bacterial reverse mutation test and in an vitro mammalian chromosomal aberration test nor was any genotoxic activity observed in an in vivo mouse micronucleus test at concentrations up to the limit dose of 2000 mg/kg bw/d. Bonolive™ did not cause mortality or toxic effects in Crl:(WI)BR Wistar rats in a 90-day repeated-dose oral toxicity study at doses of 360, 600, and 1000 mg/kg bw/d. The no observed adverse effect level in the 90-day study was 1000 mg/kg bw/d for both male and female rats, the highest dose tested.

  6. Observational Study of Travelers' Diarrhea.

    PubMed

    Meuris

    1995-03-01

    Background: European air travelers returning from Algeria, Egypt, Mexico, Morocco, and Tunisia were interviewed about their experience of travelers' diseases upon arrival in Brussels. Diarrhea was mentioned by 37% of the adults and 27% of the children. These subjects were questioned about the types of measures taken, type and duration of drug treatment (if any), and about duration of diarrhea and side effects experienced. Methods: Final analysis was performed based on 2160 interviews. The largest proportion of diarrhea was reported in the age group 15-24 years (46%). Results: The majority of the 2160 subjects had opted for drug treatment (81%): 927 subjects for loperamide alone, 235 for loperamide in combination with nifuroxazide, and 178 for nifuroxazide alone. Other drugs had been used less frequently. The median time to recovery was 2.4 days with loperamide compared to 3.2 days with nifuroxazide and to 3.4 days for the no-treatment group. Conclusions: A stratification of the results by severity of the diarrhea suggests a rank of antidiarrheal potency as follows: loperamide > nifuroxazide > no-drug treatment. The side effect with the highest incidence was constipation (2.4% with loperamide). (J Travel Med 2:11-15, 1995) Travelers' diarrhea is usually defined as the passage of at least three unformed stools per day or any number of such stools when accompanied by fever, abdominal cramping, or vomiting. The definition may be broadened to include more trivial bowel disturbance.1,2 The duration of this self-limited disease generally is 3 to 5 days. Medical intervention aims at shortening the duration of disease, thus allowing the sufferer to resume his or her usual activities at an early stage. A shortened period of recovery to physical well-being has obvious favorable economic implications if the traveler is on business and may help the maintenance of a desired level of quality of life while a traveler is on holiday. An observational study of various medical

  7. Phase I clinical and pharmacokinetic study of oral penclomedine (NSC 338720) in adults with advanced solid malignancy.

    PubMed

    Liu, Glenn; Berlin, Jordan; Tutsch, Kendra D; Van Ummersen, Lynn; Dresen, Amy; Marnocha, Rebecca; Arzomanian, Rhoda; Alberti, Dona; Feierabend, Chris; Binger, Kimberly; Wilding, George

    2002-03-01

    Penclomedine is a synthetic alpha-picoline derivative that has shown antitumor activity both in preclinical development and in Phase I work using an i.v. preparation. The main toxicities seen in those studies were dose dependent and mainly neurocerebellar, with hematological toxicity being far less severe. This Phase I trial of p.o. penclomedine was conducted to potentially alter the toxicity profile and to avoid the neurological side effects seen with i.v. penclomedine. Eligibility criteria included microscopic confirmation of a solid malignancy or lymphoma with a lack of effective anticancer therapy. Twenty patients were enrolled. The median age was 60.5 years, and the median performance status was one. All but one patient had received prior systemic therapy. The starting dose of penclomedine was 200 mg/m(2) p.o. for 5 days, and was escalated according to a traditional Fibonacci sequence until the maximum tolerated dose (MTD) was observed. No treatment-related deaths were observed during the study. The MTD was determined to be 800 mg/m(2) p.o. for 5 days. Dose-limiting toxicities included mainly neurocerebellar symptoms such as ataxia and dysmetria, but neurocortical symptoms, such as confusion, were seen as well. Myelosuppression was less common and resulted in the discontinuation of therapy in only two patients. Pharmacokinetics show that the observed MTD is consistent with the i.v. preparations, and that the bioavailability of p.o. penclomedine is 49 +/- 18%. This regimen can be considered for additional studies in patients with intracranial neoplasms, because good central nervous system penetration is evident. Further development of penclomedine metabolites, such as 4-O-demethylpenclomedine, should be considered to minimize dose-limiting neurotoxicity.

  8. Epidemiologic study of ankle fractures in a tertiary hospital

    PubMed Central

    Sakaki, Marcos Hideyo; Matsumura, Bruno Akio Rodrigues; Dotta, Thiago De Angelis Guerra; Pontin, Pedro Augusto; dos Santos, Alexandre Leme Godoy; Fernandes, Tulio Diniz

    2014-01-01

    OBJECTIVES: To evaluate the epidemiology of ankle fractures surgically treated at the Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Universidade de São Paulo. METHODS: Medical records of patients admitted with foot and ankle fractures between 2006 and 2011 were revised. Seventy three ankle fractures that underwent surgical treatment were identified. The parameters analyzed included age, gender, injured side, AO and Gustilo & Anderson classification, associated injuries, exposure, need to urgent treatment, time to definitive treatment and early post-operative complications. Study design: retrospective epidemiological study. RESULTS: Male gender was predominant among subjects and the mean age was 27.5 years old. Thirty nine fractures resulted from traffic accidents and type B fracture according to AO classification was the most common. Twenty one were open fractures and 22 patients had associated injuries. The average time to definitive treatment was 6.5 days. Early post-operative complications were found in 21.3% of patients. CONCLUSIONS: Ankle fractures treated in a tertiary hospital of a large city in Brazil affect young people victims of high-energy accidents and present significant rates of associated injuries and post-operative complications. Level of Evidence IV, Cases Series. PMID:24868187

  9. Using Transiting Exoplanets to Study Starspots with Kepler

    NASA Astrophysics Data System (ADS)

    Davenport, James R. A.; Hebb, Leslie; Hawley, Suzanne

    2015-08-01

    Starspots are a fundamental manifestation of stellar dynamos that constrain the surface magnetic field strength and topology. Kepler has already produced the first ensemble studies of starspots, discovering rotation periods and rough spot properties for thousands of stars across the main sequence. Here we study the G dwarf Kepler 17, which hosts a transiting 2.5 Jupiter mass exoplanet on a 1.5 day orbit. Starspots are frequently occulted during transit, allowing us to probe smaller-scale starspot regions on the stellar surface along the projected path of the planet. These planet-spot occultations reveal the presence of at least 7 unique starspot groups on the stellar surface at any time. The spot crossings also give an empirical estimate of the starspot temperature contrast, which we find are consistent with the Solar umbra. Using over 4 years of data for Kepler 17, we observe changes in the starspot positions and sizes indicative of differential rotation and active region diffusion. Using an MCMC-based light curve modeling code, we determine the positions and sizes of each spot group over time. Our approach is novel in modeling both the in- and out-of transit features in the light curve, allowing us to break fundamental degeneracies between spot size, latitude, and contrast. This technique constrains key properties for understanding stellar dynamos, including the stellar rotation period, differential rotation rate, and spot diffusion timescales.

  10. Study of Resource Recovery and Epidemiology in an Anaerobic Digester

    NASA Technical Reports Server (NTRS)

    Li, K. Y.; Cao, Song; Hunt, M. D.; Fu, Xuping

    1995-01-01

    Three 4-liter packed bed anaerobic digesters were fabricated and operated at 35 degrees C, pH around 7, and hydraulic retention time (HRT) of 20, 10 and 5 days to study the resource recovery and epidemiology in a controlled ecological life support system (CELSS). A simulated wastewater, consisted of shower water, clothwash water, dishwasher water, handwash water, and urine flush water was used as the feeding solution. Under steady-state operation, chemical oxygen demand (COD), total organic carbon (TOC), pH, nitrogen, phosphorus, and potassium wer monitored in the digester input and output solutions. The volume and the CH4/CO2 ratios in the biogas produced from the anaerobic digesters were measured. The results indicate about 90 percent of TOC is converted while only 5-8 percent of N-P-K are consumed in the digester. A multi-drug resistant strain of Salmonella choleraesuis was used as the indicator bacterium in the epidemiology study. The levels of Salmonella choleraesuis in the influent and the effluent wer determined and decimal decay rate constants, k(d), were estimated. The k(d) values were greater at higher initial doses than lower doses for the same HR, and greater for batch digestion (7.89/d) than for continuous digestion (4.28, 3.82, and 3.82/d for 20, 10, and 5 d HRT, respectively).

  11. Evaluation of "Myrrh extract" against Schistosoma mansoni: a histological study.

    PubMed

    Massoud, Ahmed M A; El Ebiary, Faika H; Ibrahim, Suzi H; Saleh, Hanan A A; Khalil, Hazem H M

    2010-04-01

    This study investigated the effect of myrrh extract on different developmental stages of Schistosoma mansoni. Sixty albino mice were used and divided into three main groups: GI (control group), GII (infected group) and GIII (infected-treated group). The last group was further divided into 3 subgroups where the drug was administered in a dose of 500 mg/kg body weight for 5 days starting on the 1st day PI for IIIA, on the 21st day PI for IIIB and on the 45th day PI for IIIC. A morphometric study was performed for the mean number and perimeter of granulomas. In GII, typical bilharzial granulomas were frequently encountered in the portal tracts with numerous eosinophils, collagen fiber deposition and reticular fiber condensation. Hepatocytes revealed vacuolation, nuclear affection and depletion of glycogen. In GIII, granulomas were less frequently observed with apparent decrease of eosinophils. The maximum effect of the drug was observed in SGs IIIB and IIIC as detected by significant decrease in the mean number and size of granulomas, paucity of eosinophils, decreased fibrosis and reticular fibers and the restoration of the glycogen content in the hepatocytes. The present data proved that myrrh has a valuable schistosomicidal effect against different stages of S. mansoni. This chemotherapeutic effect was more evident when the drug was given to infected mice on the 21st as well as on the 45th day PI.

  12. Epidemiologic study of neonatal jaundice. A survey of contributing factors.

    PubMed

    Bracci, R; Buonocore, G; Garosi, G; Bruchi, S; Berni, S

    1989-01-01

    In the attempt to detect factors influencing bilirubinemia in healthy full-term or near-term newborn infants, a statistical analysis was carried out on a population of 1,126 neonates to study the variables possibly associated with maximum bilirubin values reached in the first days of life. The following variables were studied: maximum bilirubin level (maxBIL), sex, mode of delivery, gestational age, birthweight, ratio of birthweight/weight on 5th day, Apgar score, Rh and ABO incompatibility. Blood glucose and calcium levels, haematocrit, intake of breast milk, formula and glucose solution were also evaluated during the first 5 days of life. Higher maxBIL was found in males compared to females, after spontaneous delivery vs. emergency caesarean section, after caesarean section without fetal distress vs. emergency caesarean section, and in ABO incompatibility vs. no ABO incompatibility. Statistically significant inverse correlations were observed between maxBIL and gestational age, birth weight, blood glucose, and SE-calcium. Significant positive correlations were found between maxBIL and haematocrit and breast milk intake. A multiple regression analysis between maxBIL and the significantly correlated parameters showed that only gestational age and birth weight remained significantly correlated with maxBIL. The results of the present investigation confirm that the factors most commonly reported as being responsible for neonatal hyperbilirubinemia do in fact play a role, although it can be considered almost negligible with the exception of gender, mode of delivery, ABO incompatibility, birthweight and gestational age.

  13. Inhalation toxicity studies with 1,3-butadiene 3 two year toxicity/carcinogenicity study in rats

    SciTech Connect

    Owen, P.E.; Glaister, J.R.; Gaunt, I.F.; Pullinger, D.H.

    1987-05-01

    Groups of 110 male and 110 female CD (Sprague-Dawley) rats were exposed to atmospheres containing 0 (control), 1000 or 8000 ppm v/v butadiene for 6 hr/day and 5 days/week. Ten of each sex from each group were killed at 52 weeks. The study was terminated when it was predicted that survival would drop to 20% to 25%. High dose rats had wet, ruffled fur and showed slight incoordination during the first exposure each week. During the second year, mortality in both treated female groups was increased because of humanitarian sacrifice of animals with large subcutaneous masses, while increased mortality in the high dose males was accompanied by an increase of the severity of nephropathy. Body weight was slightly lower than controls in both sexes at the high dose, but statistically significant only over the first 12 weeks. There were no effects in hematological analyses or tests of neuromuscular function that definitely could be associated with treatment. Liver weights at both doses were increased in both sexes with no associated pathological change. Kidney weight was increased in males at the high dose, together with an increase in the severity of nephrosis. There were increases in the incidences of pancreatic exocrine adenoma; uterine sarcoma; Zymbal gland carcinoma; mammary tumors; thyroid follicular cell tumors; and testis Leydig-cell tumors. These data suggest the butadiene is a weak oncogen to the rat under the conditions of exposure used in this study.

  14. Is social support universally adaptive in diabetes? A correlational study in an Arabic-speaking population with type 2 diabetes.

    PubMed

    Sukkarieh-Haraty, Ola; Howard, Elizabeth

    2015-01-01

    The purpose of this study was to assess the relationship between diabetes self-care, diabetes-specific emotional distress, and social support and glycemic control (hemoglobin A1C levels: HbA1c) among a sample of Lebanese adults with type 2 diabetes. A descriptive correlational design was adapted with descriptive statistics and multiple logistic regressions for analyses. A convenience sample of 140 adults diagnosed with type 2 diabetes was recruited from 2 diabetes clinics in Greater Beirut. Participants were asked to complete 4 questionnaires in Arabic. Significant associations (P < .05) were found between following a general diet for more than 3.5 days per week and higher social support and HbA1c levels of 7% or more. Social support was positively associated with HbA1c levels such that participants with uncontrolled glycemic levels, as evidenced by higher values for HbA1c, received more support from their social network.

  15. Toxicity and Safety Profiles of Methanolic Extract of Pistacia integerrima J. L. Stewart ex Brandis (PI) for Wistar Rats

    PubMed Central

    Sharwan, Gotmi; Jain, Parag; Pandey, Ravindra; Shukla, Shiv Shankar

    2016-01-01

    Objectives: The goals of this research were to evaluate acute (single-dose) and sub-acute (repeated-dose) toxicity profiles of methanolic extract of Pistacia integerrima J. L. Stewart ex Brandis (PI) for Wistar rats and to assess the safety profile of PI by observing physiological changes, mortality, changes in body weight, the histopathology of body organs, the hematology and the biochemistry of the animals. Methods: The toxicity profile of PI was evaluated using Wistar rats of both sexes. Animals were divided into four groups: Group 1; control group (normal saline), Group 2; PI-1 (250 mg/kg), Group 3; PI-2 (500 mg/kg), Group 4; PL-3 (1,000 mg/kg). An acute-toxicity study in which animals received a single dose of PI extract (2,000 mg/ kg) and were then observed for 14 days for changes in skin, fur, eye color, mucous membrane secretions and excretions, gait, posture, and tonic or clonic movements was performed according to guideline 425 of the Organization of Economic and Corporation Development (OECD). In the repeated-dose toxicity study (OECD – 407) animals received a daily dose of PI extract for 28 days (4 weeks). The parameters observed in this study include body weight, hematology and biochemistry of the animals. Results: In the acute toxicity study, no mortalities or changes in behavior were noted in the animals. The repeated-dose toxicity study was also devoid of any toxicity in the animals during the 28 days of testing with PI extract. The extract did not alter- the body weight, hematology or biochemistry of the animals. The methanolic extract of PI was to be found safe to the no-observed-adverse-effect-level (NOAEL) for the single- dose and repeated-dose toxicity tests in rats. Conclusion: The methanolic extract of PI was devoid of toxicity; hence, it can be used for various ayurvedic preparations and treatments of diseases. PMID:27695635

  16. Industrial Noise and Tooth Wear - Experimental Study

    PubMed Central

    Cavacas, Maria Alzira; Tavares, Vitor; Borrecho, Gonçalo; Oliveira, Maria João; Oliveira, Pedro; Brito, José; Águas, Artur; dos Santos, José Martins

    2015-01-01

    Tooth wear is a complex multifactorial process that involves the loss of hard dental tissue. Parafunctional habits have been mentioned as a self-destructive process caused by stress, which results in hyperactivity of masticatory muscles. Stress manifests itself through teeth grinding, leading to progressive teeth wear. The effects of continuous exposure to industrial noise, a “stressor” agent, cannot be ignored and its effects on the teeth must be evaluated. Aims: The aim of this study was to ascertain the effects of industrial noise on dental wear over time, by identifying and quantifying crown area loss. Material and Methods: 39 Wistar rats were used. Thirty rats were divided in 3 experimental groups of 10 animals each. Animals were exposed to industrial noise, rich in LFN components, for 1, 4 and 7 months, with an average weekly exposure of 40 hours (8h/day, 5 days/week with the weekends in silence). The remaining 9 animals were kept in silence. The areas of the three main cusps of the molars were measured under light microscopy. Statistical analysis used: A two-way ANOVA model was applied at significance level of 5%. Results: The average area of the molar cusps was significantly different between exposed and non-exposed animals. The most remarkable differences occurred between month 1 and 4. The total crown loss from month 1 to month 7 was 17.3% in the control group, and 46.5% in the exposed group, and the differences between these variations were significant (p<0.001). Conclusions: Our data suggest that industrial noise is an important factor in the pathogenesis of tooth wear. PMID:25798052

  17. Toxicological Evaluation of the Methanol Extract of Gmelina arborea Roxb. Bark in Mice and Rats

    PubMed Central

    Kulkarni, Y. A.; Veeranjaneyulu, A.

    2012-01-01

    Objective: The present study was designed to evaluate acute and repeated dose toxicity of the methanol extract (ME) of the Gmelina arborea stem bark. Materials and Methods: For the acute toxicity study, ME of G. arborea was orally administered to Swiss albino mice at a dose range of 300–5000 mg/kg. For the repeated dose toxicity study, the Wistar rats of either sex were orally administered with ME of G. arborea at the doses of 300, 1000, and 2000 mg/kg/day for a period of 28 days. The effects on body weight, food and water consumption, organ weight, hematology, clinical chemistry as well as histology were studied. Results: The administration of ME from the G. arborea bark at 300–5000 mg/kg did not produce mortality or significant changes in the clinical signs. The no-observed adverse effect level (NOAEL) of ME was 5000 mg/kg. There were no significant differences in the general condition, growth, organ weights, hematological parameters, clinical chemistry values, or gross and microscopic appearance of the organs from the treatment groups as compared to the control group. Conclusion: ME of G. arborea was found safe in acute and repeated dose toxicity studies when tested in mice and rats. PMID:22778509

  18. Comparative study of antidiabetic activity of Cajanus cajan and Tamarindus indica in alloxan-induced diabetic mice with a reference to in vitro antioxidant activity

    PubMed Central

    Nahar, Laizuman; Nasrin, Fatema; Zahan, Ronok; Haque, Anamul; Haque, Ekramul; Mosaddik, Ashik

    2014-01-01

    Background: Oxidative stress not only develops complications in diabetic (type 1 and type 2) but also contributes to beta cell destruction in type 2 diabetes in insulin resistance hyperglycemia. Glucose control plays an important role in the pro-oxidant/antioxidant balance. Some antidiabetic agents may by themselves have antioxidant properties independently of their role on glucose control. Objective: The present investigation draws a comparison of the protective antioxidant activity, total phenol content and the antihyperglycemic activity of the methanolic extract of Cajanus cajan root (MCC) and Tamarindus indica seeds (MTI). Materials and Methods: Antidiabetic potentials of the plant extracts were evaluated in alloxan-induced diabetic Swiss albino mice. The plant extracts at the doses of 200 and 400 mg/kg body weight was orally administered for glucose tolerance test during 1-hour study and hypoglycemic effect during 5-day study period in comparison with reference drug Metformin HCl (50 mg/kg). In vitro antioxidant potential of MCC and MTI was investigated by using 1, 1- diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity at 517 nm. Total phenolic content, total antioxidant capacity and reducing power activity was also assayed. Results: There was a significant decrease in fasting serum glucose level (P < 0.001), reduction in blood glucose level (P < 0.001) in 5-days study, observed in the alloxan-induced diabetic mice. The reduction efficacy of blood glucose level of both the extracts is proportional to their dose but MCC is more potent than MTI. Antioxidant study and quantification of phenolic compound of both the extracts revealed that they have high antioxidant capacity. Conclusion: These studies showed that MCC and MTI have both hypoglycemic and antioxidant potential but MCC is more potent than MTI. The present study suggests that both MCC and MTI could be used in managing oxidative stress. PMID:24761124

  19. Effect of city-wide sanitation programme on reduction in rate of childhood diarrhoea in northeast Brazil: assessment by two cohort studies

    PubMed Central

    Barreto, Mauricio L; Genser, Bernd; Strina, Agostino; Teixeira, Maria Gloria; Assis, Ana Marlucia O; Rego, Rita F; Teles, Carlos A; Prado, Matildes S; Matos, Sheila MA; Santos, Darci N; dos Santos, Lenaldo A; Cairncross, Sandy

    2007-01-01

    Summary Background A city-wide sanitation intervention was started in Salvador, Brazil, in 1997 to improve sewerage coverage from 26% of households to 80%. Our aim was to investigate the epidemiological effect of this city-wide sanitation programme on diarrhoea morbidity in children less than 3 years of age. Methods The investigation was composed of two longitudinal studies done in 1997–98 before the intervention (the sanitation programme) and in 2003–04 after the intervention had been completed. Each study consisted of a cohort of children (841 in the preintervention study and 1007 in the postintervention study; age 0–36 months at baseline) who were followed up for a maximum of 8 months. Children were sampled from 24 sentinel areas that were randomly chosen to represent the range of environmental conditions in the study site. At the start of each study an individual or household questionnaire was applied by trained fieldworkers; an environmental survey was done in each area before and after introduction of the sanitation programme to assess basic neighbourhood and household sanitation conditions. Daily diarrhoea data were obtained during home visits twice per week. The effect of the intervention was estimated by a hierarchical modelling approach fitting a sequence of multivariate regression models. Findings Diarrhoea prevalence fell by 21% (95% CI 18–25%)—from 9·2 (9·0–9·5) days per child-year before the intervention to 7·3 (7·0–7·5) days per child-year afterwards. After adjustment for baseline sewerage coverage and potential confounding variables, we estimated an overall prevalence reduction of 22% (19–26%). Interpretation Our results show that urban sanitation is a highly effective health measure that can no longer be ignored, and they provide a timely support for the launch of 2008 as the International Year of Sanitation. PMID:17993362

  20. Efficacy of QuadroPulse rTMS for improving motor function after spinal cord injury: Three case studies

    PubMed Central

    Alexeeva, Natalia

    2016-01-01

    Context/objective To examine the effects of repetitive QuadroPulse transcranial magnetic stimulation (rTMSQP) on hand/leg function after spinal cord injury (SCI). Design Interventional proof-of-concept study. Setting University laboratory. Participants Three adult subjects with cervical SCI. Interventions Repeated trains of magnetic stimuli were applied to the motor cortical hand/leg area. Several exploratory single-day rTMSQP protocols were examined. Ultimately we settled on a protocol using three 5-day trials of (1) rTMSQP only; (2) exercise only (targeting hand or leg function); and (3) rTMSQP combined with exercise. Outcome measures Hand motor function was assessed by Purdue Pegboard and Complete Minnesota Dexterity tests. Walking function was based on treadmill walking and the Timed Up and Go test. Electromyographic recordings were used for neurophysiological testing of cortical (by single- and double-pulse TMS) and spinal (via tendon taps and electrical nerve stimulation) excitability. Results Single-day rTMSQP application had no clear effect in the 2 subjects whose hand function was targeted, but improved walking speed in the person targeted for walking, accompanied by increased cortical excitability and reduced spinal excitability. All 3 subjects showed functional improvement following the 5-day rTMSQP intervention, an effect being even more pronounced after the five-day combined rTMSQP + exercise sessions. There were no rTMSQP-associated adverse effects. Conclusion Our findings suggest a functional benefit of motor cortical rTMSQP after SCI. The effect of rTMSQP appears to be augmented when stimulation is accompanied by targeted exercises, warranting expansion of this pilot study to a larger subject population. PMID:25437531

  1. Vitamin D Status and the Risk for Hospital-Acquired Infections in Critically Ill Adults: A Prospective Cohort Study

    PubMed Central

    Kempker, Jordan A.; West, Kathryn G.; Kempker, Russell R.; Siwamogsatham, Oranan; Alvarez, Jessica A.; Tangpricha, Vin; Ziegler, Thomas R.; Martin, Greg S.

    2015-01-01

    Introduction To identify patient characteristics associated with low serum 25-hydroxyvitamin D (25(OH)D) concentrations in the medical intensive care unit (ICU) and examine the relationship between serum 25(OH)D and the risk for hospital-acquired infections. Methods This is a prospective observational cohort of adult patients admitted to the medical ICU at an urban safety net teaching hospital in Atlanta, Georgia from November 1, 2011 through October 31, 2012 with an anticipated ICU stay ≥ 1 day. Phlebotomy for serum 25(OH)D measurement was performed on all patients within 5 days of ICU admission. Patients were followed for 30 days or until death or hospital discharge, whichever came first. Hospital-acquired infections were determined using standardized criteria from review of electronic medical record. Results Among the 314 patients analyzed, 178 (57%) had a low vitamin D at a serum 25(OH)D concentration < 15 ng/mL. The patient characteristics associated with low vitamin D included admission during winter months (28% vs. 18%, P = 0.04), higher PaO2/FiO2 (275 vs. 226 torr, P = 0.03) and a longer time from ICU admission to study phlebotomy (1.8 vs. 1.5 days, P = 0.02). A total of 36 (11%) patients were adjudicated as having a hospital-acquired infection and in multivariable analysis adjusting for gender, alcohol use, APACHE II score, time to study phlebotomy, ICU length of stay and net fluid balance, serum 25(OH)D levels < 15 ng/mL were not associated with risk for hospital-acquired infections (HR 0.85, 95% CI 0.40-1.80, P = 0.7). Conclusions In this prospective, observational cohort of adults admitted to a single-center medical ICU, we did not find a significant association between low 25(OH)D and the risk for hospital-acquired infections. PMID:25849649

  2. Analysis of semen parameters during 2 weeks of daily ejaculation: a first in humans study

    PubMed Central

    Benson, Aaron D.; Frederick, Luke; Leader, Benjamin; Tirado, Edna; Feustel, Paul; Kontio, James; McAsey, Mary; Köhler, Tobias S.

    2016-01-01

    Background Timed and frequent intercourse around the time of female ovulation is recommended to improve conception. Although a significant number of articles have examined how the length of abstinence affects these semen analysis, the effects of frequent (daily) ejaculation has not been rigorously studied. Methods Twenty normal men were recruited for daily ejaculation over 14 consecutive days, after a 3–5 days abstinence period. Semen samples were collected at the beginning of the study (day 1) and then on days 3, 7 and 14. In addition to the standard semen analysis, markers of sperm DNA quality were assessed. Results The mean age of men completing the study was 25 years (range, 23–33 years). Significant decreases were observed in mean semen volume, total motile count (TMC) and sperm concentration during the study period without significant changes in motility or morphology. A large initial change in ejaculate volume, TMC and sperm concentration provided the primary difference in these values over the study period, with a plateau in values after this initial decrease (after study day 3). Metrics of DNA integrity did not change in a statistically or clinically meaningful way during the study period. Conclusions While a small study, this represents the most extensive examination of sperm quality with daily ejaculation. These findings generally support an approach of a short period of abstinence followed by daily copulation around ovulation to maximize the number of sperm available and optimize conception. PMID:27785432

  3. Positive association between short-term ambient air pollution exposure and children blood pressure in China-Result from the Seven Northeast Cities (SNEC) study.

    PubMed

    Zeng, Xiao-Wen; Qian, Zhengmin Min; Vaughn, Michael G; Nelson, Erik J; Dharmage, Shyamali C; Bowatte, Gayan; Perret, Jennifer; Chen, Duo-Hong; Ma, Huimin; Lin, Shao; de Foy, Benjamin; Hu, Li-Wen; Yang, Bo-Yi; Xu, Shu-Li; Zhang, Chuan; Tian, Yan-Peng; Nian, Min; Wang, Jia; Xiao, Xiang; Bao, Wen-Wen; Zhang, Ya-Zhi; Dong, Guang-Hui

    2017-05-01

    The impact of ambient air pollution on health causes concerns in China. However, little is known about the association of short-term air pollution exposure with blood pressure (BP) in children. The goal of present study was to assess the association between short-term air pollution and BP in children from a highly polluted area in China. This study enrolled 9354 children in 24 elementary and middle schools (aged 5-17 years) from the Seven Northeast Cities (SNEC) study, respectively, during the period of 2012-2013. Ambient air pollutants, including particulate matter with an aerodynamic diameter of ≤10 μm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3) on the days (1-5 days) preceding BP examination were collected from local air monitoring stations. Generalized additive models and two-level regression analyses were used to evaluate the relationship between air pollution and BP after adjusting for other covariates. Results showed that with an interquartile range (IQR) increase in PM10 (50.0 μg/m(3)) and O3 (53.0 μg/m(3)) level during the 5-day mean exposure, positive associations with elevated BP were observed, with an odds ratio of 2.17 (95% CI, 1.61-2.93) for PM10 and 2.77 (95% CI, 1.94-3.95) for O3. Both systolic BP and diastolic BP levels were positively associated with an IQR increase of four air pollutants at different lag times. Specifically, an IQR increase in the 5-day mean of PM10 and O3 was associated with elevation of 2.07 mmHg (95% CI, 1.71-2.44) and 3.29 mmHg (95% CI, 2.86-3.72) in systolic BP, respectively. When stratified by sex, positive relationships were observed for elevated BP with NO2 exposure only in males. This is the first report on the relationship between ambient short-term air pollution exposure and children BP in China. Findings indicate a need to control air pollutants and protect children from heavy air pollution exposure in China.

  4. Study of skin rashes after antibiotic use in young children.

    PubMed

    Huang, S W; Borum, P R

    1998-10-01

    Immunoglobulin E (IgE)-mediated drug sensitivity in children is uncommon. However, undefined skin rash following antibiotic ingestion in younger children is commonly observed in clinical practice. We studied 86 consecutively referred patients to our allergy clinic over a 5-year period. We found that the majority of children (80%) with skin rashes were under 3 years of age. All the children had been treated with antibiotics for a bacterial upper respiratory infection (URI; otitis media, sinusitis, or pharyngitis), 73 (85%) had erythematous rash, 13 (15%) had urticaria occurring 3-5 days after the treatment, and 43 (50%) reported a repeated rash with the use of two or more different antibiotics. There were no reports of systemic reactions or histories of accompanying food allergy. When patients were given the suspected antibiotics while they were well, none developed rash. However, in the next bacterial infection, 62 (72%) chose to receive dye-free suspensions of the suspected antibiotics. Only three patients (3.5%) elected for the dye-containing suspension. Of the 62 patients who received dye-free suspensions, only eight developed a mild skin rash, which was managed successfully. We conclude that a practical approach for non-IgE-mediated skin rash needs to be evaluated. The current practice of complete avoidance of the suspected antibiotics without further evaluation may be unwarranted.

  5. Studies of the mortality rate of Culicoides imicola in Morocco.

    PubMed

    Baylis, M; Touti, J; Bouayoune, H; Moudni, L; Taoufiq, B; el Hasnaoui, H

    1998-01-01

    Daily mortality rates of female Culicoides imicola were found for eight sites in Morocco in 1994 and for six sites in 1995. The mortality rates were found by operating Pirbright-type light traps for a number of consecutive nights in late summer or autumn and finding the parous rate assuming a feeding interval of 3 to 5 days. The mortality rates were calculated according to established methods. In Morocco the daily mortality rates were found to vary from about 5% per day (Arbaoua, 1994, 1995 and Sidi Moussa 1995) up to 20-25% per day (Berkane, Marrakech, Tangier). In general, estimates of daily mortality rate were consistent between the two years of study. Among sites, daily mortality rate was significantly correlated with the average night-time minimum wind speed but not mean or maximum night-time wind speeds, or with temperature, humidity or saturation deficit. The observed mortality rates suggest that at Arbaoua, were 1,000 flies to become infected with African horse sickness virus, at least 330 would live long enough to take 3 or more infective blood meals on hosts. At Berkane, the survival rate per 1,000 is less than 10. In general, the pattern observed for daily mortality rate, combined with the relative population sizes of C. imicola in Morocco, agree well with the observed distribution of African horse sickness in the country during the 1989-1991 epizootic.

  6. Natural history of human calicivirus infection: a prospective cohort study.

    PubMed

    Rockx, Barry; De Wit, Matty; Vennema, Harry; Vinjé, Jan; De Bruin, Erwin; Van Duynhoven, Yvonne; Koopmans, Marion

    2002-08-01

    We investigated the natural history of human Calicivirus infection in the community. Clinical information was obtained from 99 subjects infected with Norwalk-like viruses (NLV) and 40 subjects infected with Sapporo-like viruses (SLV) in a prospective, community-based cohort study. NLV infection was common in all age groups, whereas SLV infection was mainly restricted to children aged <5 years. Symptoms lasted for a median of 5 and 6 days for NLV and SLV infections, respectively. Disease was characterized by diarrhea during the first 5 days (87% of patients with NLV infection and 95% of patients with SLV infection) and vomiting on the first day (74% for NLV and 60% for SLV). Vomiting was less common in children aged <1 year (59% for NLV and 44% for SLV) than it was among children aged >/=1 year (>75% for NLV and >67% for SLV). Overall, NLV was detected in 26% of patients up to 3 weeks after the onset of illness. This proportion was highest (38%) for children aged <1 year. SLV shedding subsided after 14 days. These data show that the durations of disease and viral shedding of caliciviruses are longer than has been described elsewhere. Therefore, the impact of these infections may have been underestimated.

  7. Clinical analgesic assay of repeated and single doses of heroin and hydromorphone.

    PubMed

    Wallenstein, S L; Houde, R W; Portenoy, R; Lapin, J; Rogers, A; Foley, K M

    1990-04-01

    A direct comparison of the analgesic activities of heroin and hydromorphone was carried out in cancer patients with postsurgical pain. Intramuscular doses of 5 and 10 mg of heroin were compared with 1 and 2 mg of hydromorphone in a randomized, double-blind, 4-point parallel group assay. Design innovations in the study provided that about half the patients would receive prior repeated doses of the same drug as the test medication, and half would receive the alternate medication. Both test drugs were found to be potent, relatively short acting analgesics with similar profiles of action. Hydromorphone was about 5 times as potent as heroin on a milligram basis. The comparison of those patients who had repeated doses of the same treatment prior to the test dose and those who had repeated doses of the alternate drug demonstrated no significant effect on the relative potency estimates. Side effect occurrence was similar for both drugs, with sleepiness the most prominent effect. The study supports the view that hydromorphone and heroin produce similar clinical effects, and that either drug may adequately substitute for the other. Covariate analysis indicated that time since last analgesic was positively related to analgesia, and amount of prior opioid had a negative relationship. To a lesser extent, increase in patient age was associated with an increase in analgesic scores. Taking these covariates into account served to increase the sensitivity of the analysis.

  8. [Treatment in the event of antibiotic prophylaxis failure in gynecologic surgery. A retrospective study of 20 cases].

    PubMed

    Paparella, P; Zullo, M A; Astorri, A L; Bondì, M; Maglione, A; Oliva, C; Mancuso Bondì, S

    1994-09-01

    A retrospective study was performed of the type of treatment used in 20 patients undergoing gynecological surgery in whom antibiotic prophylaxis with Mezlocillin (2 g i.v.) had failed. Patients were subdivided into three groups: A) Initial therapy with Mezlocillin (8 patients, 2 g/die i.m.) or Cefotetan (2 patients, 2 g/die i.m.) and subsequent addition of Gentamicin (8 patients, 240 mg/die i.m.) or Tobramycin (2 patients, 200 mg/die i.m.) and subsequently Metronidazole (7 patients, 1.5 g/die per os). B) Therapy with Imipenem/Cilastatin (6 patients, 1.5 g/die i.m.). C) Therapy with Imipenem/Cilastatin (4 patients, 1.5 g/die i.m.) after a variety of antibiotics: Cotrimoxazole (Trimethoprim 160 mg/die and sulphamethoxazole 800 mg/die per os), Pefloxacin (800 mg/die per os), Cefotetan (2 g/die i.m.) and Mezlocillin (2 g/die i.m.). Time taken to lower temperature was shorter in Group B (3.5 days) compared to Group A (6.8 days) and Group C (10 days). Postoperative hospital stay was also shorter in Group B (9 days) compared to Group C (16.5 days) and Group A (11.1 days). The immediate administration of an antibiotic active against Gram+ and Gram- germs, aerobes and anaerobes is therefore useful in the event of failure of antibiotic prophylaxis, rather than the use in succession of associations of antibiotics with a limited spectrum.

  9. Influence of Erosive and Abrasive Cycling on Bonding of Different Adhesive Systems to Enamel: An In situ Study.

    PubMed

    Giacomini, Marina Ciccone; Casas-Apayco, Leslie Caroll; Machado, Camila Moreira; Freitas, Maria Cristina Carvalho de Almendra; Atta, Maria Teresa; Wang, Linda

    2016-01-01

    This study evaluated the impact of orange juice on the bond strength (BS) of dentin bonding systems (DBSs) to enamel surface after simulation with an in situ/ ex vivo erosive cycling. One hundred and ninety two bovine enamel fragments (4x4x2mm) were obtained and randomized regarding superficial microhardness and distributed to palatal devices for 8 volunteers, in three phases (one for each DBS), containing 8 blocks, which were, allocated in 4 pairs. Daily, these pairs were subjected extraorally to the following conditions: CONT- neither erosive nor abrasive challenge; ERO- erosive challenge only; ABR- abrasive challenge only and ERO + ABR- with erosive and abrasive challenges. Erosive cycles (immersion in orange juice, 3 times/day/5 min/5 days) or/and abrasive challenges (electric toothbrush, 3 times/day/1 min/5 days) were performed. After these cycles, all specimens were restored with the adhesive systems Adper Scotchbond Multi Purpose (MP), Adper Single Bond 2 (SB) or Clearfil SE Bond (SE), and the composite resin Filtek Z250. After 7 days, sticks (area ≅1 mm2) were obtained and subjected to the microtensile bond strength test (μTBS) at 0.5 mm/min. Data was statistically analyzed by ANOVA and Tukey tests (a=0.05). Failure modes were determined using a digital microscope (40´). DBS was the only statistical significant factor. SE was the unique DBS not affected in any challenge, whereas MP and SB performed according to the scenario. The adhesive and mixed failures were predominant in all groups. Overall performance suggested that BS to enamel after erosive /abrasive challenged by orange juice was not affected and it was material-dependent.

  10. Efficacy evaluation of Bauhinia variegata L. stem bark powder as adjunct therapy in chronic Staphylococcus aureus mastitis in goat

    PubMed Central

    Dash, Jeevan Ranjan; Sar, Tapas Kumar; Samanta, Indranil; Pal, Subodh; Khan, Madhuchhanda; Patra, Nimai Charan; Sarkar, Uttam; Maji, Asit Kumar; Mandal, Tapan Kumar

    2014-01-01

    Objective: The objective was to study the effect of Bauhinia variegata L. stem bark powder as adjunct therapy in chronic Staphylococcus aureus mastitis in goat. Materials and Methods: Mastitis was induced by intracisternal inoculation of coagulase positive S. aureus (J638) at the concentration of 2000 colony forming units. Group I animals were treated with repeated dose of ceftriaxone at 20 mg/kg intravenously, and Group II animals were treated with once daily oral administration of B. variegata L. stem bark powder at 6 g/kg for 7 days followed by maintenance dose at 3 g/kg for next 7 days along with repeated dose of the antibiotic at 20 mg/kg intravenously at 4 days interval. Results: No significant improvement in the clinical condition of the udder was noticed in the group treated with repeated dose of ceftriaxone alone. However, in the group treated with B. variegata L. stem bark powder along with repeated dose of ceftriaxone, no S. aureus colony was seen at 96 h and onwards in milk samples with a marked decrease in somatic cell count and milk alkaline phosphatase activity and increased lactoperoxidase activity. Further, plasma and milk concentration of ceftriaxone/ceftizoxime was increased, which indicated antibacterial, bioenhancing and antiinflammatory properties of the bark powder. The Group II animals also exhibited marked reduction in polymorphonuclear cells and fibrous tissue indicating antifibrotic property of B. variegata L. Conclusion: B. variegata L. stem bark powder can be considered as an effective adjunct therapy to intravenous ceftriaxone in S. aureus chronic mastitis in goat. PMID:25298668

  11. Study of disbudding goat kids following injection of clove oil essence in horn bud region.

    PubMed

    Molaei, Mohammad Mahdi; Mostafavi, Ali; Kheirandish, Reza; Azari, Omid; Shaddel, Mohsen

    2015-01-01

    This study was performed to evaluate the efficacy of injection of essential oil of Eugenia caryophyllata in the kid horn buds, as a new chemical technique for disbudding. Five-day-old healthy goat kids from both sexes (n = 16) were divided randomly into 4 equal groups. In groups 1, 2 and 3, 0.2 mL of clove essence and in group 4 (control) 0.2 mL of normal saline was injected into the left horn bud of goat kids. Right horn bud in all kids was considered to ensure that they are horned. During the study, the rate of horn growth were evaluated in determined time intervals between groups 1 and 4. Tissue samples were taken from right and left horn bud in groups 2 and 3, at five and ten days after clove essence injection, for microscopic study. The results of the study showed that the clove essence stopped horn growth, whereas there was no significant difference in horn growth rate between left and right horns after injection of normal saline, in group 4. Histopathological study showed that injection of clove essence caused complete necrosis of epidermis and underlying dermis with collagenolysis in horn bud tissues, 5 days after injection and then progress in healing process was observed after 10 days. According to the results of this study, it can be concluded that the injection of clove essence is an effective method to stop horn growth without any undesirable effects on clinical parameters in goat kids.

  12. Ergonomic study of an operator's work of a molybdenum plant.

    PubMed

    Oñate, Esteban; Meyer, Felipe

    2012-01-01

    This study was part of an ergonomic program which is being carried out through an agreement between the University of Concepción and a Chilean private mining company. The purpose of this case study was to identify working conditions in which the physical and mental workload could be over the capabilities of the operator. He was responsible for loading trucks with sacks of molybdenum and for downloading reagents and handles them. The methods employed in this study included electronic records, interviews, surveys, review of the company standards, a time study and physical and mental workload analysis. Results showed that 84% of the time the operator was carrying out principal and secondary activities and no break periods were detected. It was found that the pace of work and the shift system generated unfavorable conditions by imbalance in the workload on the different days of the week. In the light of the results recommendations were made for a number of ergonomic changes. Most of them were accepted by the company. The most important achievement was a change in the shift system. The overload of the operator was due to the fact that he was in a shift working 5 days and resting on weekends. The imbalance was mainly because the work of the week end was accumulated for Monday. As a result of the study, the company contracted a second worker for this job and adopted a 7x7 shift system, meaning that they work seven days and rest seven days. An evaluation carried out two month after adopting the new shift revealed that changes were well accepted by the worker.

  13. Assessing the mammalian toxicity of high-boiling petroleum substances under the rubric of the HPV program.

    PubMed

    Gray, Thomas M; Simpson, Barry J; Nicolich, Mark J; Murray, F Jay; Verstuyft, Allen W; Roth, Randy N; McKee, Richard H

    2013-11-01

    In 1998, the US EPA announced the HPV Challenge Program, a voluntary chemical data collection effort. The Petroleum HPV Testing Group (PHPVTG(1)) volunteered to provide data on approximately 110 high boiling petroleum substances (HBPS), i.e. substances with final boiling points ≥ approximately 650°F (343°C). These HBPS are substances of unknown and variable composition (UVCBs) that are composed of numerous individual constituents. Toxicity studies have shown that some HBPS can produce systemic (repeat-dose) and developmental effects, and some are mutagenic under in vitro conditions. The papers in this supplement show that these effects are related to the profiles of aromatic constituents in these substances. Further, it is shown that the effects on selected repeat-dose and developmental toxicity endpoints and mutagenic activity in bacterial assays can be predicted from compositional information using models based on the aromatic-ring class profile, "ARC profile" as defined by gas chromatographic separation of the DMSO-soluble fraction of the starting materials. This chromatographic method and the predictive models provide an efficient means of characterizing for screening purposes the potential for repeat-dose, developmental effects and bacterial mutagenicity of HBPS and can reduce the number of animal tests that would be required if these tests were conducted on all 110 HBPS.

  14. Accumulation and effects of nodularin from a single and repeated oral doses of cyanobacterium Nodularia spumigena on flounder (Platichthys flesus L.).

    PubMed

    Vuorinen, Pekka J; Sipiä, Vesa O; Karlsson, Krister; Keinänen, Marja; Furey, Ambrose; Allis, Orla; James, Kevin; Perttilä, Ulla; Rimaila-Pärnänen, Eija; Meriluoto, Jussi A O

    2009-07-01

    Nodularin (NODLN) is a cyclic pentapeptide hepatotoxin produced by the cyanobacterium Nodularia spumigena, which occurs regularly in the Baltic Sea during the summer season. In this study flounder (Platichthys flesus L.) was orally exposed to NODLN either as a single dose or as three repeated doses 3 days apart. Liver and bile samples of the fish were taken 4 days after the last dose. Liver glutathione-S-transferase (GST) activity was also measured and the histopathology of the liver was investigated. The liver of the exposed fish was analyzed by liquid chromatography-mass spectrometry for NODLN concentration. The content of NODLN-like compounds in the bile was analyzed by enzyme-linked immunosorbent assay. NODLN exposure caused slightly incoherent liver architecture and degenerative cell changes in both groups. The mean liver GST activity was significantly higher in the repeatedly dosed flounders than in the singly dosed flounders or in the control. In conclusion, the significantly lower NODLN concentration and the increased GST activity in the liver of the repeatedly dosed flounders compared to the singly dosed flounders suggest that NODLN is rapidly detoxificated. The absence of NODLN glutathione conjugates and the low concentrations of NODLN-like compounds in the bile indicate that detoxification products disintegrate or they are rapidly excreted.

  15. Safety evaluation of chitosan and chitosan acid salts from Panurilus argus lobster.

    PubMed

    Lagarto, Alicia; Merino, Nelson; Valdes, Odalys; Dominguez, Jesus; Spencer, Evelyn; de la Paz, Nilia; Aparicio, Guillermo

    2015-01-01

    Chitosan is a natural polymer with excellent properties such as biocompatibility, biodegradability, non-toxicity and adsorptive abilities. We obtained chitosan derived from Panurilus argus lobster shell and its lactate and acetate salts to introduce in pharmaceutical industry. We examined the single and repeated dose toxicity of chitosan and its lactate and acetate salts. Single oral doses of 2000 mg/kg were well tolerated for all three materials. In the repeat dose tests, animals treated with chitosan only show a slight erythrocytes increase. Variations in erythrocyte and leukocyte count and some biochemical parameters were observed in animals treated with chitosan acid salts. One g/kg orally was found to be the subacute NOAEL for chitosan due to the hematological findings observed were not considered adverse. Chitosans obtained from Panurilus argus lobster shell have low toxicity and may be safe in rats because it did not cause any lethality or changes in the general behavior in both the single and repeated dose toxicity studies.

  16. Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy young and elderly subjects: comparison with elderly rheumatic patients.

    PubMed Central

    Taylor, I W; Chasseaud, L F; Taylor, T; James, I; Dorf, G; Darragh, A

    1991-01-01

    The pharmacokinetics of ximoprofen were studied in young and elderly subjects after single and repeated doses up to 30 mg. In healthy elderly subjects (30 mg dose), a mean peak plasma drug concentration of 1.78 micrograms ml-1 +/- 0.83 s.d. occurred at a mean time of 1.95 h +/- 1.40 s.d. and, thereafter, concentrations declined monoexponentially with a mean half-life of 3.8 h +/- 1.4 s.d. Comparison of these data with those from younger healthy subjects showed that peak drug concentrations, areas under the curve and half-lives were about two-fold greater in the elderly, these differences probably reflecting a lower systemic drug clearance. Similar results were obtained on comparing data from young healthy subjects and elderly rheumatic patients receiving single and repeated doses of ximoprofen (15 mg twice daily). In patients, the half-life of ximoprofen was 2.5 h +/- 0.7 s.d. Within either group, pharmacokinetic parameters after single or repeated doses were similar: ximoprofen did not accumulate in the plasma of the young or elderly. PMID:1931475

  17. Comparison of Capillary and Venous Plasma Drug Concentrations After Repeated Administration of Risperidone, Paliperidone, Quetiapine, Olanzapine, or Aripiprazole

    PubMed Central

    De Meulder, Marc; Ariyawansa, Jay; Savitz, Adam

    2016-01-01

    Abstract Quantification of blood levels of antipsychotic drugs may be useful for managing medication therapy. This open‐label, parallel‐group study was performed to compare finger‐stick‐based capillary with corresponding venous plasma concentrations for risperidone, paliperidone, quetiapine, olanzapine, and aripiprazole and their major metabolites after repeated dosing in patients with schizophrenia or related illnesses. Finger‐stick‐based capillary and venous blood samples were collected at various times within a dosing interval. All drug concentration measurements in the derived plasma samples were performed with validated liquid chromatography–tandem mass spectrometry methods. Finger‐stick‐based capillary and venous plasma drug concentrations after repeated dosing were generally similar. Olanzapine capillary plasma concentrations, however, were on average approximately 20% higher than venous concentrations, with a trend for a relatively greater difference occurring shortly after dosing. In addition, smaller capillary–venous differences were observed for extended‐release and long‐acting intramuscular formulations and for aripiprazole, a drug with a long half‐life, compared with drugs administered as an immediate‐release formulation (risperidone, olanzapine). After repeated dosing, plasma derived from finger‐stick‐based blood was observed to be predictive of the venous concentrations. Capillary sampling may be an appropriate alternative to venous sampling to readily evaluate systemic drug concentrations. PMID:27363344

  18. Development of temporally refined land-use regression models predicting daily household-level air pollution in a panel study of lung function among asthmatic children.

    PubMed

    Johnson, Markey; Macneill, Morgan; Grgicak-Mannion, Alice; Nethery, Elizabeth; Xu, Xiaohong; Dales, Robert; Rasmussen, Pat; Wheeler, Amanda

    2013-01-01

    Regulatory monitoring data and land-use regression (LUR) models have been widely used for estimating individual exposure to ambient air pollution in epidemiologic studies. However, LUR models lack fine-scale temporal resolution for predicting acute exposure and regulatory monitoring provides daily concentrations, but fails to capture spatial variability within urban areas. This study coupled LUR models with continuous regulatory monitoring to predict daily ambient nitrogen dioxide (NO(2)) and particulate matter (PM(2.5)) at 50 homes in Windsor, Ontario. We compared predicted versus measured daily outdoor concentrations for 5 days in winter and 5 days in summer at each home. We also examined the implications of using modeled versus measured daily pollutant concentrations to predict daily lung function among asthmatic children living in those homes. Mixed effect analysis suggested that temporally refined LUR models explained a greater proportion of the spatial and temporal variance in daily household-level outdoor NO(2) measurements compared with daily concentrations based on regulatory monitoring. Temporally refined LUR models captured 40% (summer) and 10% (winter) more of the spatial variance compared with regulatory monitoring data. Ambient PM(2.5) showed little spatial variation; therefore, daily PM(2.5) models were similar to regulatory monitoring data in the proportion of variance explained. Furthermore, effect estimates for forced expiratory volume in 1 s (FEV(1)) and peak expiratory flow (PEF) based on modeled pollutant concentrations were consistent with effects based on household-level measurements for NO(2) and PM(2.5). These results suggest that LUR modeling can be combined with continuous regulatory monitoring data to predict daily household-level exposure to ambient air pollution. Temporally refined LUR models provided a modest improvement in estimating daily household-level NO(2) compared with regulatory monitoring data alone, suggesting that this

  19. Postoperative opioid sparing with injectable hydroxypropyl-β-cyclodextrin-diclofenac: pooled analysis of data from two Phase III clinical trials

    PubMed Central

    Gan, Tong J; Singla, Neil; Daniels, Stephen E; Hamilton, Douglas A; Lacouture, Peter G; Reyes, Christian RD; Carr, Daniel B

    2017-01-01

    Purpose Use of nonopioid analgesics (including nonsteroidal anti-inflammatory drugs) for postoperative pain management can reduce opioid consumption and potentially prevent opioid-related adverse events. This study examined the postoperative opioid-sparing effect of repeated-dose injectable diclofenac formulated with hydroxypropyl-β-cyclodextrin (HPβCD)-diclofenac. Patients and methods Pooled data from two double-blind, randomized, placebo- and active comparator-controlled Phase III trials were analyzed. Patients received HPβCD-diclofenac, placebo, or ketorolac by intravenous injection every 6 hours for up to 5 days following abdominal/pelvic or orthopedic surgery. Rescue opioid use was evaluated from the time of first study drug administration to up to 120 hours following the first dose in the overall study population and in subgroups defined by baseline pain severity, age, and HPβCD-diclofenac dose. Results Overall, 608 patients received ≥1 dose of study medication and were included in the analysis. While 93.2% of patients receiving placebo required opioids, the proportion of patients requiring opioids was significantly lower for patients receiving HPβCD-diclofenac (18.75, 37.5, or 50 mg) or ketorolac (P<0.005 for all comparisons). Mean cumulative opioid dose and number of doses were significantly lower among patients receiving HPβCD-diclofenac versus placebo for the 0–24 through 0–120 hour time periods (P<0.0001), as well as versus ketorolac for the 0–72 through 0–120 hour time periods (P<0.05). HPβCD-diclofenac significantly reduced opioid consumption versus placebo in subgroups based on baseline pain severity (moderate, severe) and age (<65 years, ≥65 years) from the 0–24 hour period onward. When compared to ketorolac, HPβCD-diclofenac also significantly reduced cumulative opioid consumption among patients with moderate baseline pain (0–72 through 0–120 hours) and opioid dose number among patients ≥65 years old (0–24 through 0

  20. A STUDY OF FISCHER 344 RATS EXPOSED TO SILICA DUST FOR SIX MONTHS AT CONCENTRATIONS OF 0, 2, 10 OR 20 MG / M3.

    SciTech Connect

    KUTZMAN,R.S.

    1984-02-01

    The major objective of this study was to relate the results of a series of functional tests to the compositional and structural alterations in the rat lung induced by subchronic exposure to silica dust. Fischer-344 rats were exposed for 6 hours/day, 5 days/week for 6 months to either 0, 2, 10, or 20 mg SiO{sub 2}/m{sup 3}. The general appearance of the exposed rats was not different from that of the controls. Interestingly, female rats exposed to silica dust, at all tested concentrations, gained more weight than the controls. The lung weight and the lung-to-body weight ratio was greater in the male rats exposed to the highest concentration of silica dust.

  1. Thermo-mechanical processing of sugar beet pulp. III. Study of extruded films improvement with various plasticizers and cross-linkers.

    PubMed

    Rouilly, A; Geneau-Sbartaï, C; Rigal, L

    2009-06-01

    Thermoplastic sugar beet pulp (thermo-mechanical processing was discussed in previous studies) was formed into film strips by extrusion. Film tensile properties are discussed according to the molecular structure of external plasticizer. Sorbitol, fructose and adipic acid have a marked antiplasticizing effect, while urea and xylitol gave higher ultimate tensile stress than glycerol for a comparable strain at break. Xylitol can be considered as the best plasticizer with UTS and EL of, respectively, 4.9 MPa and 11.3% and water absorption (85% RH, 25 degrees C) was less than 25%. Glycidyl methacrylate was directly used in the extrusion process as cross-linker. In high humidity atmosphere (97% RH, 25 degrees C), film water absorption was then kept under 40% while tensile strength and strain were improved of 50% and with a 30 min UV post-treatment the mass gain in absorption was even less than 30% after 5 days.

  2. Study of enrofloxacin depletion in the eggs of laying hens using diphasic dialysis extraction/purification and determinative HPLC-MS analysis.

    PubMed

    Lolo, M; Pedreira, S; Fente, C; Vázquez, B I; Franco, C M; Cepeda, A

    2005-04-20

    A study of the depletion of enrofloxacin residues in eggs was carried out using a diphasic dialysis procedure for the extraction of fluoroquinolone residues from the matrix. Enrofloxacin was administered to laying hens through the intramuscular route (15 mg/day) and orally (12 mg/day). After daily collection, the egg albumen and the egg yolk were separated, and the residue levels were determined using an HPLC-MS (API-ESI) method. The enrofloxacin and ciprofloxacin peaks gradually increased until the fifth day, because the drug was employed for 5 days. However, differences were observed in the depletion curves of enrofloxacin and its metabolite when both parts of the egg and the mode of administration were considered.

  3. High dose cytarabine plus gemtuzumab ozogamicin for patients with relapsed or refractory acute myeloid leukemia: Cancer and Leukemia Group B study 19902.

    PubMed

    Stone, Richard M; Moser, Barry; Sanford, Ben; Schulman, Philip; Kolitz, Jonathan E; Allen, Steven; Stock, Wendy; Galinsky, Ilene; Vij, Ravi; Marcucci, Guido; Hurd, David; Larson, Richard A

    2011-03-01

    Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate, was combined with high dose cytarabine (HiDAC; cytarabine 3g/m(2) over 3h daily for 5 days) for adults with relapsed or refractory AML. HiDAC plus GO 9mg/m(2) on day 7 and 4.5mg/m(2) on day 14 was not tolerated, but HiDAC followed by GO 9mg/m(2) on day 7 was safe: 12/37 (32%) patients with relapsed AML achieved complete remission. Median overall survival was 8.9 months. No grade 4 hepatic veno-occlusive disease was observed. This regimen merits further study, both in this setting and as a remission consolidation therapy.

  4. SLICER Airborne Laser Altimeter Characterization of Canopy Structure and Sub-canopy Topography for the BOREAS Northern and Southern Study Regions: Instrument and Data Product Description

    NASA Technical Reports Server (NTRS)

    Hall, Forrest G. (Editor); Nickeson, Jaime (Editor); Harding, D. J.; Blair, J. B.; Rabine, D. L.; Still, K. L.

    2000-01-01

    SLICER data were acquired in support of BOREAS at all of the TF sites in the SSA and NSA, and along transects between the study areas. Data were acquired on 5 days between 18-Jul and 30-Jul-1996. Each coverage of a tower site is typically 40 km in length, with a minimum of 3 and a maximum of 10 lines across each tower oriented in a variety of azimuths. The SLICER data were acquired simultaneously with ASAS hyperspectral, multiview angle images. The SLICER Level 3 products consist of binary files for each flight line with a data record for each laser shot composed of 13 parameters and a 600-byte waveform that is the raw record of the backscatter laser energy reflected from Earth's surface. The SLICER data are stored in a combination of ASCII and binary data files.

  5. Study of pineapple peelings processing into vinegar by biotechnology.

    PubMed

    Sossou, Seyram K; Ameyapoh, Yaovi; Karou, Simplice D; de Souza, Comlan

    2009-06-01

    This study aimed to reduce post-harvest losses of pineapple local variety egbenana by the transformation of juice into vinegar through biotechnological process. Vinegar was produced through two successive fermentations: alcoholic and acetic fermentations. The alcohol fermentation was carried out at 30 degrees C using yeast. Biomass, pH and Brix were evaluated daily during the fermentation. Acetic fermentation was carried out at 30 degrees C using an acetic bacteria strain isolated from pineapple wine previously exposed to ambient temperature (28 degrees C) for 5 days. Biomass, pH and acid levels were monitored each 2 days. The performance of acetic bacteria isolated was also assessed by studying their glucose and ethanol tolerance. The study allowed the isolation of yeast coded Saccharomyces cerevisiae (LAS01) and an acetic bacteria coded Acetobacter sp. (ASV03) both occurring in the pineapple juice. The monitoring of successive fermentations indicated that the pineapple juice with sugar concentration of 20 Brix, seeded with 10(6) cells of Saccharomyces cerevisiae (LAS01) for alcoholic fermentation for 4 days and afterwards seeded with 10(6) cells of Acetobacter sp. resulted in 4.5 acetic degree vinegar at Brix 5.3% and pH 2.8 for 23 to 25 days. The study of glucose tolerance of the strain of Acetobacter sp. showed that the growth of acetic bacteria was important in a juice with high concentration of sugar. However, the concentration of ethanol did not effect on the acetic bacteria growth. These results enabled on one hand to improve the manufacturing technology of vinegar from fruits and on the other hand to produce a starter of yeast and acetic bacteria strains for this production.

  6. Acute, 2-week, and 13-week inhalation toxicity studies on dimethylethoxysilane vapor in Fischer 344 rats.

    PubMed

    Dodd, D E; Stuart, B O; Rothenberg, S J; Kershaw, M; Mann, P C; James, J T; Lam, C W

    1994-01-01

    Dimethylethoxysilane (DMES), a volatile liquid, is used by NASA to waterproof the heat-protective silica tiles and blankets on the Space Shuttle. Acute, 2-wk, and 13-wk inhalation exposures to DMES vapor were conducted in male and female Fischer 344 rats. In the acute study, rats were exposed to 4000, 2000, 1000, 500, or 0 (control) ppm DMES for 4 h and observed for 14 days. There were no deaths. Narcosis and ataxia were observed in rats of the two highest concentrations only. These signs disappeared within 1 h following exposure. There were no DMES-related gross or microscopic tissue lesions in rats of all exposure groups. In the 2-wk study, rats were exposed for 6 h/day, 5 days/wk to 3000, 1000, 300, 100, or 0 ppm DMES. During exposure, narcosis was observed in rats of the 3000 and 1000 ppm groups. There was a mild decrease in body weight gain in rats of the 3000 ppm group. A decrease in platelet count, an increase in bile acids, and reduced weights of the thymus, testis, and liver were observed in rats of the 3000 ppm group. Microscopically, hypospermatogenesis and spermatid giant cells were observed in the seminiferous tubules of the testes of rats exposed to 3000 ppm DMES. In the 13-wk study, rats were exposed 6 h/day, 5 days/wk to 2000, 600, 160, 40, or 0 ppm DMES. During exposure, rats of the 2000 ppm group exhibited mild narcosis and loss of startle reflex. Recovery from these central nervous system signs was rapid. Body weights were mildly decreased for rats of the 2000 ppm group. There were no exposure-related effects in hematology, serum chemistry, or urinalysis. Female rats of the 2000 ppm group had delayed estrous cycles (6 days compared to 5 days in control rats). Noteworthy organ weight changes in rats of the 2000 ppm group included decreases in thymus, liver, and testicular weights; however, pathologic lesions were observed in the testes only. Sperm motility, epididymal sperm count, and testicular spermatid count were dramatically reduced

  7. Acute, 2-week, and 13-week inhalation toxicity studies on dimethylethoxysilane vapor in Fischer 344 rats

    NASA Technical Reports Server (NTRS)

    Dodd, D. E.; Stuart, B. O.; Rothenberg, S. J.; Kershaw, M.; Mann, P. C.; James, J. T.; Lam, C. W.

    1994-01-01

    Dimethylethoxysilane (DMES), a volatile liquid, is used by NASA to waterproof the heat-protective silica tiles and blankets on the Space Shuttle. Acute, 2-wk, and 13-wk inhalation exposures to DMES vapor were conducted in male and female Fischer 344 rats. In the acute study, rats were exposed to 4000, 2000, 1000, 500, or 0 (control) ppm DMES for 4 h and observed for 14 days. There were no deaths. Narcosis and ataxia were observed in rats of the two highest concentrations only. These signs disappeared within 1 h following exposure. There were no DMES-related gross or microscopic tissue lesions in rats of all exposure groups. In the 2-wk study, rats were exposed for 6 h/day, 5 days/wk to 3000, 1000, 300, 100, or 0 ppm DMES. During exposure, narcosis was observed in rats of the 3000 and 1000 ppm groups. There was a mild decrease in body weight gain in rats of the 3000 ppm group. A decrease in platelet count, an increase in bile acids, and reduced weights of the thymus, testis, and liver were observed in rats of the 3000 ppm group. Microscopically, hypospermatogenesis and spermatid giant cells were observed in the seminiferous tubules of the testes of rats exposed to 3000 ppm DMES. In the 13-wk study, rats were exposed 6 h/day, 5 days/wk to 2000, 600, 160, 40, or 0 ppm DMES. During exposure, rats of the 2000 ppm group exhibited mild narcosis and loss of startle reflex. Recovery from these central nervous system signs was rapid. Body weights were mildly decreased for rats of the 2000 ppm group. There were no exposure-related effects in hematology, serum chemistry, or urinalysis. Female rats of the 2000 ppm group had delayed estrous cycles (6 days compared to 5 days in control rats). Noteworthy organ weight changes in rats of the 2000 ppm group included decreases in thymus, liver, and testicular weights; however, pathologic lesions were observed in the testes only. Sperm motility, epididymal sperm count, and testicular spermatid count were dramatically reduced

  8. Toxicology Studies on Lewisite and Sulfur Mustard Agents: Two-Generation Reproduction Study of Lewisite in Rats Final Report

    SciTech Connect

    Sasser, L. B.; Cushing, J. A.; Kalkwarf, D. R.; Mellick, P. W.; Buschbom, R. L.

    1989-07-15

    Occupational health standards have not been established for Lewisite [bis(2-chlorethyl)arsine], a potent toxic vesicant which reacts with the sulfhydryl groups of proteins through its arsenic group. The purposes of this study were to determine the reproductive consequences and dose~response of continuing Lewisite exposure of parental males and females and their offspring in a 42-week two-generation study. Solutions of Lewisite were prepared for administration by diluting the neat agent with sesame oil. Rats were administered Lewisite (0, 0.10, 0.25 or 0.60 mg/kg/day for 5 days a week) via intragastric intubation prior to mating, during mating and after mating until the birth of their offspring. The dams continued to receive Lewisite during lactation. At weaning, male and female offspring of each group were selected to continue on the study; rece1v1ng Lewisite during adolescence, mating and throughout gestation. Again, the dams continued to receive Lewisite until weaning of the offspring. Lewisite had no adverse effect on reproduction performance, fertility or reproductive organ weights of male or female rats through two consecutive generations. No adverse effect to offspring were attributed to Lewisite exposure. Minor changes in growth was the only maternal effect observed. Lewisite exposure of parental rats caused no gross or microscopic lesions in testes, epididymis, prostrate, seminal vesicles, ovaries, uterus or vagina. Severe inflammation of the lung was observed at necropsy in cases in which Lewisite gained access to the respiratory system from accidental dosing or reflux and aspiration; this usually caused early death of the animal. The NOEL for reproductive effects in this study was greater than 0.60 mg/kg/day.

  9. SBOTE study: extracorporeal shock wave therapy versus electrical stimulation after botulinum toxin type a injection for post-stroke spasticity-a prospective randomized trial.

    PubMed

    Santamato, Andrea; Notarnicola, Angela; Panza, Francesco; Ranieri, Maurizio; Micello, Maria Francesca; Manganotti, Paolo; Moretti, Biagio; Fortunato, Francesca; Filoni, Serena; Fiore, Pietro

    2013-02-01

    Research is on-going to identify new methods of biostimulation to increase the effect of botulinum toxin type A (BTX-A) in the treatment of spasticity. The Spasticity treated by Botulinum Toxin and ESWT (SBOTE) study is a prospective, randomized controlled trial assessing the effectiveness of extracorporeal shock wave therapy (ESWT) given immediately after BTX-A injections compared with electrical stimulation (ES) given immediately after BTX-A therapy for the management of focal upper limb spasticity in stroke patients. ES was given for 30 min twice a day for 5 days starting at 5 Hz; ESWT was given once a day for 5 days. At study follow-up, patients treated with BTX-A injections and ESWT showed a statistically greater significance and continuous decrease of spasticity measure (modified Ashworth scale [MAS]: 1.37, 1.75 and 1.58 at 15, 30 and 90 days post-treatment, respectively), of spasms (spasm frequency scale [SFS]: 0.8 and 0.25 at 30 and 90 days post-treatment, respectively) and of pain (visual analogue scale [VAS]: 1.94 and 1.87 at 30 and 90 days, respectively) compared with patients treated with BTX-A injections and ES (MAS: 2.37, 2.18 and 2.18, respectively) (p < 0.05) (SFS: 1.5 and 1.06, respectively) (p < 0.05) (VAS: 2.44 and 2.69 respectively) (p < 0.05). ESWT enhances the effect of BTX-A to a greater extent than ES, probably by modulating rheology of the muscle and neurotransmission at the neuromuscular junction.

  10. Association with meteo-climatological factors and daily emergency visits for renal colic and urinary calculi in Cuneo, Italy. A retrospective observational study, 2007-2010

    NASA Astrophysics Data System (ADS)

    Condemi, Vincenzo; Gestro, Massimo; Dozio, Elena; Tartaglino, Bruno; Corsi Romanelli, Massimiliano Marco; Solimene, Umberto; Meco, Roberto

    2015-03-01

    The incidence of nephrolithiasis is rising worldwide, especially in women and with increasing age. Incidence and prevalence of kidney stones are affected by genetic, nutritional, and environmental factors. The aim of this study is to investigate the link between various meteorological factors (independent variables) and the daily number of visits to the Emergency Department (ED of the S. Croce and Carle Hospital of Cuneo for renal colic (RC) and urinary stones (UC) as the dependent variable over the years 2007-2010. The Poisson generalized regression models (PGAMs) have been used in different progressive ways. The results of PGAMs (stage 1) adjusted for seasonal and calendar factors confirmed a significant correlation ( p < 0.03) with the thermal parameter. Evaluation of the dose-response effect [PGAMs combined with distributed lags nonlinear models (DLNMs)—stage 2], expressed in terms of relative risk (RR) and cumulative relative risk (RRC), indicated a relative significant effect up to 15 lag days of lag (RR > 1), with a first peak after 5 days (lag ranges 0-1, 0-3, and 0-5) and a second weak peak observed along the 5-15 lag range days. The estimated RR for females was significant, mainly in the second and fourth age group considered (19-44 and >65 years): RR for total ED visits 1.27, confidence interval (CI) 1.11-1.46 (lag 0-5 days); RR 1.42, CI 1.01-2.01 (lag 0-10 days); and RR 1.35, CI 1.09-1.68 (lag 0-15 days). The research also indicated a moderate involvement of the thermal factor in the onset of RC caused by UC, exclusively in the female sex. Further studies will be necessary to confirm these results.

  11. Short-term effects of repetitive transcranial magnetic stimulation on sleep bruxism – a pilot study

    PubMed Central

    Zhou, Wei-Na; Fu, Hai-Yang; Du, Yi-Fei; Sun, Jian-Hua; Zhang, Jing-Lu; Wang, Chen; Svensson, Peter; Wang, Ke-Lun

    2016-01-01

    The purpose of this study was to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on patients with sleep bruxism (SB). Twelve patients with SB were included in an open, single-intervention pilot study. rTMS at 1 Hz and an intensity of 80% of the active motor threshold was applied to the ‘hot spot' of the masseter muscle representation at the primary motor cortex bilaterally for 20 min per side each day for 5 consecutive days. The jaw-closing muscle electromyographic (EMG) activity during sleep was recorded with a portable EMG recorder at baseline, during rTMS treatment and at follow-up for 5 days. In addition, patients scored their jaw-closing muscle soreness on a 0–10 numerical rating scale (NRS). Data were analysed with analysis of variance. The intensity of the EMG activity was suppressed during and after rTMS compared to the baseline (P = 0.04; P = 0.02, respectively). The NRS score of soreness decreased significantly during and after rTMS compared with baseline (P < 0.01). These findings indicated a significant inhibition of jaw-closing muscle activity during sleep along with a decrease of muscle soreness. This pilot study raises the possibility of therapeutic benefits from rTMS in patients with bruxism and calls for further and more controlled studies. PMID:27025267

  12. Short-term effects of repetitive transcranial magnetic stimulation on sleep bruxism - a pilot study.

    PubMed

    Zhou, Wei-Na; Fu, Hai-Yang; Du, Yi-Fei; Sun, Jian-Hua; Zhang, Jing-Lu; Wang, Chen; Svensson, Peter; Wang, Ke-Lun

    2016-03-30

    The purpose of this study was to investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on patients with sleep bruxism (SB). Twelve patients with SB were included in an open, single-intervention pilot study. rTMS at 1 Hz and an intensity of 80% of the active motor threshold was applied to the 'hot spot' of the masseter muscle representation at the primary motor cortex bilaterally for 20 min per side each day for 5 consecutive days. The jaw-closing muscle electromyographic (EMG) activity during sleep was recorded with a portable EMG recorder at baseline, during rTMS treatment and at follow-up for 5 days. In addition, patients scored their jaw-closing muscle soreness on a 0-10 numerical rating scale (NRS). Data were analysed with analysis of variance. The intensity of the EMG activity was suppressed during and after rTMS compared to the baseline (P = 0.04; P = 0.02, respectively). The NRS score of soreness decreased significantly during and after rTMS compared with baseline (P < 0.01). These findings indicated a significant inhibition of jaw-closing muscle activity during sleep along with a decrease of muscle soreness. This pilot study raises the possibility of therapeutic benefits from rTMS in patients with bruxism and calls for further and more controlled studies.

  13. Oseltamivir Population Pharmacokinetics in the Ferret: Model Application for Pharmacokinetic/Pharmacodynamic Study Design.

    PubMed

    Reddy, Micaela B; Yang, Kuo-Hsiung; Rao, Gauri; Rayner, Craig R; Nie, Jing; Pamulapati, Chandrasena; Marathe, Bindumadhav M; Forrest, Alan; Govorkova, Elena A

    2015-01-01

    The ferret is a suitable small animal model for preclinical evaluation of efficacy of antiviral drugs against various influenza strains, including highly pathogenic H5N1 viruses. Rigorous pharmacokinetics/pharmacodynamics (PK/PD) assessment of ferret data has not been conducted, perhaps due to insufficient information on oseltamivir PK. Here, based on PK data from several studies on both uninfected and influenza-infected groups (i.e., with influenza A viruses of H5N1 and H3N2 subtypes and an influenza B virus) and several types of anesthesia we developed a population PK model for the active compound oseltamivir carboxylate (OC) in the ferret. The ferret OC population PK model incorporated delayed first-order input, two-compartment distribution, and first-order elimination to successfully describe OC PK. Influenza infection did not affect model parameters, but anesthesia did. The conclusion that OC PK was not influenced by influenza infection must be viewed with caution because the influenza infections in the studies included here resulted in mild clinical symptoms in terms of temperature, body weight, and activity scores. Monte Carlo simulations were used to determine that administration of a 5.08 mg/kg dose of oseltamivir phosphate to ferret every 12 h for 5 days results in the same median OC area under the plasma concentration-time curve 0-12 h (i.e., 3220 mg h/mL) as that observed in humans during steady state at the approved dose of 75 mg twice daily for 5 days. Modeling indicated that PK variability for OC in the ferret model is high, and can be affected by anesthesia. Therefore, for proper interpretation of PK/PD data, sparse PK sampling to allow the OC PK determination in individual animals is important. Another consideration in appropriate design of PK/PD studies is achieving an influenza infection with pronounced clinical symptoms and efficient virus replication, which will allow adequate evaluation of drug effects.

  14. Developmental toxicity (dominant lethal mutation) study on agent lewisite. Dominant lethal study of lewisite in male rats. Final report, 15 September 1988-14 June 1990

    SciTech Connect

    Bucci, T.J.; Parker, R.M.; Dacre, J.C.; Denny, K.H.

    1993-12-01

    Lewisite (dichloro(2-chlorovinyl)arsine, Agent L) was investigated as part of the US Army Toxicological Program on Chemical Agents. The study was conducted during January - April, 1990. Dosing was performed during 3-12 January, 1990. Twenty male CD rats per dose group were given 1.5, 0.75 or 0.375 mg/kg Lewisite or vehicle control (one ml sesame seed oil) daily by gavage for 5 days. Positive control males were given one ml sesame seed oil by gavage on Day 1-4 and on Day 5 they were given an intraperitoneal injection of 100 mg/kg ethyl methanesulphonate, a known mutagen. Each male was mated to two virgin females (12 weeks of age) per counted and the uteri and contents were examined. Implantation sites were categorized as live/dead fetuses or early/late resorption. No significant differences inreproductive indices were seen between treatment groups and the control group with the exception of the positive control. Males were killed during Week 13 and necropsied. Sperm morphology/modify, testicular histopathologic evaluation and morphometric analysis of seminiferous tubule cross-sections revealed no differences among Lewisite-treated rats and rats given sesame seed oil. There was no indication of a dominant lethal mutagenic or other toxic effect on the male reproductive tract as a result of exposure to Lewisite, under the conditions of this study. The No Observable Adverse Effect Level was the highest dose used, 1.500 mg/kg.

  15. Salzburg Skiing for the Elderly Study: study design and intervention--health benefit of alpine skiing for elderly.

    PubMed

    Müller, E; Gimpl, M; Poetzelsberger, B; Finkenzeller, T; Scheiber, P

    2011-08-01

    The aim of this study was to monitor the long-term effects of skiing on the health-related parameters of older individuals. This paper describes the overall study design and the intervention phase. The study utilized a randomized control group design consisting of an intervention group (n=27; age: 67.5 ± 2.8 years) and a control group (n=20; age: 67.3 ± 4.4 years). Parameters of interest were measured during pre-, post- and retention-test sessions. The intervention phase lasted for 12 weeks, with an average of 28.5 days of guided skiing. Daily heart rate (HR) profiles and global positioning system data throughout the ski day were recorded. Perceived exertion levels as well as mood status of the subjects were recorded regularly. The intervention group completed an average of 4885 vertical meters of downhill skiing, with a total skiing distance of 40.5 km/day. In the skiing phase, the average physiological load was 72.4 ± 8.9% of HR(max) . The dimension "positive mood" referred to skiing (on scale of 0-10), with an average value of 7.6 ± 1.7 after skiing. The dimension of "negative mood" was much less pronounced, having a mean of 1.1 ± 1.5 after skiing. Two subjects suffered injuries while falling during skiing. The effects of the 12-week skiing intervention on the tested parameters will be reported in the following papers of this supplementum.

  16. Alpine Skiing With total knee ArthroPlasty (ASWAP): study design and intervention.

    PubMed

    Kösters, A; Pötzelsberger, B; Dela, F; Dorn, U; Hofstaedter, T; Fink, C; Müller, E

    2015-08-01

    The aim of this study was to monitor the long-term effects of skiing on health-related parameters and implant related factors like loosening and wear in patients with total knee arthroplasty. This paper describes the overall study design, general demographics, and physiological demand of the intervention phase. A control group design consisting of an intervention group (n = 14; age: 70.4 ± 4.5 years) and a control group (n = 17; age: 71.5 ± 5.1 years) was utilized in this study. Parameters of interest were measured during pre-, post-, and retention test sessions. During the 12 weeks of intervention, an average of 25.5 days of guided skiing was conducted by each patient. Daily heart rate (HR) profiles and global positioning system data throughout the ski day were recorded. The intervention group completed an average of 3393 vertical meters of downhill skiing, with a total skiing distance of 33.6 km/day. Average skiing speed was 8.2 m/s. In the skiing phase, the average physiological load was 75.9 ± 6.6% of HRmax . Further effects of the 12-week skiing intervention on the tested parameters will be reported in the following papers of this supplementum.

  17. Glyphosate degradation by immobilized bacteria: field studies with industrial wastewater effluent.

    PubMed

    Hallas, L E; Adams, W J; Heitkamp, M A

    1992-04-01

    Immobilized bacteria have been shown in the laboratory to effectively remove glyphosate from wastewater effluent discharged from an activated sludge treatment system. Bacterial consortia in lab columns maintained a 99% glyphosate-degrading activity (GDA) at a hydraulic residence time of less than 20 min. In this study, a pilot plant (capacity, 45 liters/min) was used for a field demonstration. Initially, activated sludge was enriched for microbes with GDA during a 3-week biocarrier activation period. Wastewater effluent was then spiked with glyphosate and NH4Cl and recycled through the pilot plant column during start-up. Microbes with GDA were enhanced by maintaining the pH at less than 8 and adding yeast extract (less than 10 mg/liter). Once the consortia were stabilized, the column capacity for glyphosate removal was determined in a 60-day continuous-flow study. Waste containing 50 mg of glyphosate per liter was pumped at increasing flow rates until a steady state was reached. A microbial GDA of greater than 90% was achieved at a 10-min hydraulic residence time (144 hydraulic turnovers per day). Additional studies showed that microbes with GDA were recoverable within (i) 5 days of an acid shock and (ii) 3 days after a 21-day dormancy (low-flow, low-maintenance) mode. These results suggest that full-scale use of immobilized bacteria can be a cost-effective and dependable technique for the biotreatment of industrial wastewater.

  18. Low-level laser therapy: Case-control study in dogs with sterile pyogranulomatous pododermatitis

    PubMed Central

    Perego, Roberta; Proverbio, D.; Zuccaro, A.; Spada, E.

    2016-01-01

    Aim: Low-level laser therapy (LLLT) is a therapeutic photobiostimulation with properties in reducing swelling, inflammation, and promoting tissue healing. The objective of this pilot study was to evaluate LLLT in sterile pyogranulomatous pododermatitis in five dogs. Materials and Methods: In each dog, one lesion was designated as the control (treated with a 0.0584% hydrocortisone aceponate spray), and one or more other lesions were treated with a gallium aluminum arsenide-laser, daily for 5 days. Lesions were scored before treatment (D0), at the end (D4), 16 days after the last laser treatment (D20), and after 2 months (D65). Results: Comparing the treated lesion group with the control lesion group, the clinical score was similar at D0, whereas there was a statistically significant difference at D4 and D20; in the treated group over time, there was a statistically significant improvement between D0, D4, and D20. Lesion recurrence was absent in more than 50% of the treated lesions at D65. No adverse reactions were reported. Conclusion: Given the positive results of this first clinical study, it would be interesting to extend the study to confirm the validity of this type of therapy in sterile pyogranulomatous pododermatitis in the dog. PMID:27651678

  19. Need satisfaction and employees' recovery state at work: A daily diary study.

    PubMed

    van Hooff, Madelon L M; Geurts, Sabine A E

    2015-07-01

    The present study aimed to advance insight in the associations between employees' daily effort expenditure at work and their recovery state during the workday, and specifically focused on the role of daily work-related need satisfaction in this process. We examined (a) if high intrinsic work motivation and low self-control effort act as mediating mechanisms underlying the beneficial role of need satisfaction, and (b) to what extent need satisfaction mitigates the adverse effects of high job demands (work pressure and cognitive demands) on employee recovery. Data were collected by means of a 5-day daily diary study (2 measurements daily: in the morning before work, and at the end of the workday) among 68 participants. Multilevel analyses showed that need satisfaction at work was related to a beneficial recovery state at the end of the workday, and that this association was mediated by high intrinsic work motivation and low self-control effort. Furthermore, need satisfaction attenuated the adverse effects of high work pressure on employee recovery. All in all, this study increased our understanding of employees' daily effort and recovery processes at work, and highlighted the beneficial role of need satisfaction at work.

  20. Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection.

    PubMed

    Kohno, Shigeru; Yen, Muh-Yong; Cheong, Hee-Jin; Hirotsu, Nobuo; Ishida, Tadashi; Kadota, Jun-ichi; Mizuguchi, Masashi; Kida, Hiroshi; Shimada, Jingoro

    2011-11-01

    Antiviral medications with activity against influenza viruses are important in controlling influenza. We compared intravenous peramivir, a potent neuraminidase inhibitor, with oseltamivir in patients with seasonal influenza virus infection. In a multinational, multicenter, double-blind, double-dummy randomized controlled study, patients aged ≥ 20 years with influenza A or B virus infection were randomly assigned to receive either a single intravenous infusion of peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day [b.i.d.] for 5 days). To demonstrate the noninferiority of peramivir in reducing the time to alleviation of influenza symptoms with hazard model analysis and a noninferiority margin of 0.170, we planned to recruit 1,050 patients in South Korea, Japan, and Taiwan. A total of 1,091 patients (364 receiving 300 mg and 362 receiving 600 mg of peramivir; 365 receiving oseltamivir) were included in the intent-to-treat infected population. The median durations of influenza symptoms were 78.0, 81.0, and 81.8 h in the groups treated with 300 mg of peramivir, 600 mg of peramivir, and oseltamivir, respectively. The hazard ratios of the 300- and 600-mg-peramivir groups compared to the oseltamivir group were 0.946 (97.5% confidence interval [CI], 0.793, 1.129) and 0.970 (97.5% CI, 0.814, 1.157), respectively. Both peramivir groups were noninferior to the oseltamivir group (97.5% CI, <1.170). The overall incidence of adverse drug reactions was significantly lower in the 300-mg-peramivir group, but the incidence of severe reactions in either peramivir group was not different from that in the oseltamivir group. Thus, a single intravenous dose of peramivir may be an alternative to a 5-day oral dose of oseltamivir for patients with seasonal influenza virus infection.

  1. A Phase II study of preoperative radiotherapy and concomitant weekly irinotecan in combination with protracted venous infusion 5-fluorouracil, for resectable locally advanced rectal cancer

    SciTech Connect

    Navarro, Matilde . E-mail: mnavarrogarcia@ico.scs.es; Dotor, Emma; Rivera, Fernando; Sanchez-Rovira, Pedro; Vega-Villegas, Maria Eugenia; Cervantes, Andres; Garcia, Jose Luis; Gallen, Manel; Aranda, Enrique

    2006-09-01

    Purpose: The aim of this study was to evaluate the efficacy and tolerance of preoperative chemoradiotherapy (CRT) with irinotecan (CPT-11) and 5-fluorouracil (5-FU) in patients with resectable rectal cancer. Methods and Materials: Patients with resectable T3-T4 rectal cancer and Eastern Cooperative Oncology Group performance status <2 were included. CPT-11 (50 mg/m{sup 2} weekly) and 5-FU (225 mg/m{sup 2}/day continuous infusion, 5 days/week) were concurrently administered with radiation therapy (RT) (45 Gy, 1.8 Gy/day, 5 days/week), during 5 weeks. Results: A total of 74 patients were enrolled: mean age, 59 years (20-74 years; SD, 11.7). Planned treatment was delivered to most patients (median relative dose intensity for both drugs was 100%). Grade 3/4 lymphocytopenia occurred in 35 patients (47%), neutropenia in 5 (7%), and anemia in 2 (3%). Main Grade 3 nonhematologic toxicities were diarrhea (14%), asthenia (9%), rectal mucositis (8%), and abdominal pain (8%). Of the 73 resected specimens, 13.7% (95% confidence interval [CI], 6.8-23.7) had a pathologic complete response and 49.3% (95% CI, 37.4-61.3) were downstaged. Additionally, 66.7% (95% CI, 51.1-80.0) of patients with ultrasound staged N1/N2 disease had no pathologic evidence of nodal involvement after CRT. Conclusions: This preoperative CRT schedule has been shown to be effective and feasible in a large population of patients with resectable rectal cancer.

  2. Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors

    PubMed Central

    Do, Khanh; Wilsker, Deborah; Ji, Jiuping; Zlott, Jennifer; Freshwater, Tomoko; Kinders, Robert J.; Collins, Jerry; Chen, Alice P.; Doroshow, James H.; Kummar, Shivaani

    2015-01-01

    Purpose Wee1 tyrosine kinase phosphorylates and inactivates cyclin-dependent kinase (Cdk) 1/2 in response to DNA damage. AZD1775 is a first-in-class inhibitor of Wee1 kinase with single-agent antitumor activity in preclinical models. We conducted a phase I study of single-agent AZD1775 in adult patients with refractory solid tumors to determine its maximum-tolerated dose (MTD), pharmacokinetics, and modulation of phosphorylated Tyr15-Cdk (pY15-Cdk) and phosphorylated histone H2AX (γH2AX) levels in paired tumor biopsies. Patients and Methods AZD1775 was administered orally twice per day over 2.5 days per week for up to 2 weeks per 21-day cycle (3 + 3 design). At the MTD, paired tumor biopsies were obtained at baseline and after the fifth dose to determine pY15-Cdk and γH2AX levels. Six patients with BRCA-mutant solid tumors were also enrolled at the MTD. Results Twenty-five patients were enrolled. The MTD was established as 225 mg twice per day orally over 2.5 days per week for 2 weeks per 21-day cycle. Confirmed partial responses were observed in two patients carrying BRCA mutations: one with head and neck cancer and one with ovarian cancer. Common toxicities were myelosuppression and diarrhea. Dose-limiting toxicities were supraventricular tachyarrhythmia and myelosuppression. Accumulation of drug (t1/2 approximately 11 hours) was observed. Reduction in pY15-Cdk levels (two of five paired biopsies) and increases in γH2AX levels (three of five paired biopsies) were demonstrated. Conclusion This is the first report of AZD1775 single-agent activity in patients carrying BRCA mutations. Proof-of-mechanism was demonstrated by target modulation and DNA damage response in paired tumor biopsies. PMID:25964244

  3. A prospective study to assess the implementation of a fast-track system to meet the two-week target for colorectal cancer in Somerset.

    PubMed

    Davies, R. J.; Ewings, P.; Welbourn, R.; Collins, C.; Kennedy, R.; Royle, C.

    2002-01-01

    OBJECTIVE: This prospective study assesses the introduction of a fast-track referral system for patients with suspected colorectal cancer. PATIENTS AND METHODS: The referral system was initiated in Yeovil District Hospital and Taunton and Somerset Hospital using six screening criteria to select high-risk patients. Data on all high-risk patients from 1 November 1999 to 30 April 2000 was recorded prospectively. Patients with proven colorectal cancer diagnosed between 1 November 1998 and 30 April 1999 have been identified for comparison. RESULTS: There were 158 new cases of colorectal cancer in total (111 elective, 47 emergency). 59 cases of colorectal cancer were diagnosed from 433 fast-track referrals (53% of total elective cases). Median time from referral to diagnosis in the fast-track group was 11 days vs. 32.5 days for nonfast-track elective patients (P < 0.001). Median time from referral to diagnosis for all elective cases was 17 days vs. 38.5 days for patients presenting one year earlier (P < 0.001). 75% of fast-track patients were diagnosed with colorectal cancer within two weeks, compared with 17% of nonfast-track elective patients (P < 0.001). The proportion of emergency admissions was reduced from 40% to 30% (P=0.07) following the introduction of this system. CONCLUSION: Data from the first six months reveal that over half of the elective cases of colorectal cancer were diagnosed within the fast-track system. The median time from referral to diagnosis in these patients was within two weeks and there has been a significant reduction in the time to diagnosis associated with the introduction of this service.

  4. Biotransformation and nephrotoxicity of ochratoxin B in rats

    SciTech Connect

    Mally, Angela; Keim-Heusler, Heike; Amberg, Alexander; Kurz, Michael; Zepnik, Herbert; Mantle, Peter; Voelkel, Wolfgang; Hard, Gordon C.; Dekant, Wolfgang . E-mail: dekant@toxi.uni-wuerzburg.de

    2005-08-01

    Ochratoxin B (OTB), a secondary metabolite of Aspergillus ochraceus, is the nonchlorinated analogue of the mycotoxin ochratoxin A (OTA), which is one of the most potent renal carcinogens in rodents. Despite the closely related structure, OTB is considered to be of much lower toxicity. OTA is poorly metabolized and slowly eliminated, and this may play an important role in OTA toxicity, carcinogenicity, and organ specificity. Since little is known regarding biotransformation and renal toxicity of OTB, the aim of this study was to investigate biotransformation of OTB in rats and to characterize the nephrotoxicity and cytotoxicity of OTB. Male F344 rats were administered either a single dose of OTB (10 mg/kg bw) or repeated doses (2 mg/kg bw, 5 days/week for 2 weeks) and euthanized 72 h after the last dosing. In proximal tubule cells of animals treated with a single high dose of OTB, a slight increase in mitotic figures was observed, but no treatment-related changes were evident in clinical chemistry, in renal function, and histopathology after repeated administration. Excretion of OTB and metabolites in urine and feces was analyzed using both HPLC with fluorescence detection and LC-MS/MS. Ochratoxin beta, which results from cleavage of the peptide bond, was the major metabolite excreted in urine in addition to small amounts of 4-hydroxy-OTB. In total, 19% of the administered dose was recovered as OTB and ochratoxin beta in urine and feces within 72 h after a single dose. In contrast to OTA, no tissue-specific retention of OTB was evident after single and repeated administration. In LLC-PK1 cells, a renal cell culture system that retains much of the specific features of the proximal tubule, only minor differences in the extent of cytotoxicity of OTA and OTB were observed. At low concentrations (< 25 {mu}M), treatment with OTA was slightly more toxic, whereas reduction in cell viability was similar at concentrations up to 100 {mu}M. In summary, these data suggest that

  5. Antiamoebic chemoprophylaxis using quinfamide in children: a comparative study.

    PubMed

    Padilla, Nicolas; Diaz, Rosalinda; Alarcon, Alfonso; Barreda, Roberto

    2002-04-20

    This study sought to examine whether the administration of quinfamide at 3- or 6-month intervals diminished the frequency of Entamoeba histolytica cysts in stool samples compared to controls. The prospective, longitudinal, randomized, single-blind study examined children from six primary schools in Celaya and Neutla, Guanajuato. Of the 1,524 students in these schools, we selected participants for the study as follows: Children were included in the study if their parents agreed in writing to the study and if the children demonstrated evidence of E. histolytica cysts after a parasitoscopic analysis by concentration (PSC) in three samples over consecutive days using Faust"s method. Those included in the study received a single 4.3-g/kg dose of quinfamide, and we performed PSC on days 5, 6, and 7 following dose administration to examine whether quinfamide had affected the presence of the cysts. The study participants who tested negative for cysts were divided into three groups: Group 1 had 102 patients who underwent quinfamide treatment and three CPS analyses after the 12 months of the study; Group 2 had 98 subjects who underwent the quinfamide treatment and three CPS analyses at months 3, 6, 9, and 12 after their entrance into the study; and Group 3 had 102 patients, who underwent the quinfamide treatment and series of three CPS analyses at months 6 and 12 of the study. All participants received the dose of quinfamide after providing stool samples and after a clinical gastrointestinal history was obtained. Further clinical gastrointestinal data were collected 5 days after the quintamide dose was administered. We used EpiInfo 6.0 for statistical analysis, calculating c2 and p values for the clinical data and the CPS data after the 12 months concluded. Of the initial samples of 1,524 subjects, 308 (20.2%) had Entamoebic cysts. Of these, six were further eliminated because they did not meet the inclusion requirements. At the conclusion of the study, Group 1 presented

  6. Modified Sequential Therapy Regimen versus Conventional Triple Therapy for Helicobacter Pylori Eradication in Duodenal Ulcer Patients in China: A Multicenter Clinical Comparative Study

    PubMed Central

    Zhou, Ying-Qun; Xu, Ling; Wang, Bing-Fang; Fan, Xiao-Ming; Wu, Jian-Ye; Wang, Chun-Yan; Guo, Chuan-Yong; Xu, Xuan-Fu

    2012-01-01

    Objective. Antimicrobial resistance has decreased eradication rates for Helicobacter pylori infection worldwide. To observe the effect of eradicating Helicobacter pylori (H. pylori) and the treatment of duodenal ulcer by 2 kinds of modified sequential therapy through comparing with that of 10-day standard triple therapy. Methods. A total of 210 patients who were confirmed in duodenal ulcer active or heal period by gastroscopy and H. pylori positive confirmed by rapid urease test, serum anti-H. pylori antibody (ELASE), or histological examination enrolled in the study. All the patients were randomly divided into three groups: group A (70 cases) and group B (70 cases) were provided 10-day modified sequential therapy; group C (70 cases) was provided 10-day standard triple therapy. Patients of group A received 20 mg of Esomeprazole, 500 mg of Clarithromycin for the first 5 days, followed by 20 mg of Esomeprazole, 500 mg of Clarithromycin, and 1000 mg of Amoxicillin for the remaining 5 days. Group B received 20 mg of Esomeprazole, 1000 mg of Amoxicillin for the first 5 days, followed by 20 mg of Esomeprazole, 500 mg of Clarithromycin, and 1000 mg of Amoxicillin for the remaining 5 days. Group C received 20 mg of Esomeprazole, 500 mg of Clarithromycin, and 1000 mg of Amoxicillin for standard 10-day therapy. All drugs were given twice daily. H. pylori eradication rate was checked four to eight weeks after taking the medicine by using a 13C urea breath test. In the first, second, third, seventh, twenty-first, thirty-fifth days respectively, the symptoms of patients such as epigastric gnawing, burning pain, and acidity were evaluated simultaneously. Results. Overall, 210 patients accomplished all therapy schemes, 9 case patients were excluded. The examination result indicated that the H. pylori eradication rate of each group was as follows: group A 92.5% (62/67), group B 86.8% (59/68), and group C 78.8% (52/66). The H. pylori eradication rate of

  7. Biofeasibility Study.

    ERIC Educational Resources Information Center

    Chaparian, Michael

    1995-01-01

    Discusses the use of bioremediation as a method for disposing of contaminants by exploiting natural biodegradation processes. The process of conducting a biofeasibility study and a case study are reviewed. (LZ)

  8. Cystometric study

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/003904.htm Cystometric study To use the sharing features on this page, please enable JavaScript. Cystometric study measures the amount of fluid in the bladder ...

  9. Intelligence Studies

    ERIC Educational Resources Information Center

    Monaghan, Peter

    2009-01-01

    To make an academic study of matters inherently secret and potentially explosive seems a tall task. But a growing number of scholars are drawn to understanding spycraft. The interdisciplinary field of intelligence studies is mushrooming, as scholars trained in history, international studies, and political science examine such subjects as the…

  10. Religious Studies.

    ERIC Educational Resources Information Center

    Mohrman, Kathryn, Ed.

    1980-01-01

    An essay on the study of religion at the college level and descriptions of nine programs of religious studies are presented. The essay by David C. Smith suggests that while traditional goals continue to be important, especially in church-related colleges, religious studies has expanded to include insights and materials from such disciplines as…

  11. College Studying.

    ERIC Educational Resources Information Center

    Nist, Sherrie L.; Simpson, Michele

    2002-01-01

    Notes that many students enter postsecondary institutions unprepared to meet the studying demands placed on them. Examines models and taxonomies that have guided researchers as they have investigated studying. Reviews research factors related to studying at the college level: course characteristics, learner characteristics, and learning…

  12. Social Studies.

    ERIC Educational Resources Information Center

    Bieber, Edward

    The product of a Special Studies Institute, this teacher developed resource guide for the emotionally handicapped (K-6) presents social study concepts and activities relative to education in the urban out-of-doors. Focus is on the study of man (past, present, and future) interacting with his environment. Listed below are activity examples: (1)…

  13. Suppression of BDNF-induced expression of neuropeptide Y (NPY) in cortical cultures by oxygen-glucose deprivation: a model system to study ischemic mechanisms in the perinatal brain.

    PubMed

    Barnea, Ayalla; Roberts, Jodie

    2002-04-15

    The aim of this study was to establish a culture system that can serve as a model to study hypoxic-ischemic mechanisms regulating the functional expression of NPY neurons in the perinatal brain. Using an aggregate culture system derived from the rat fetal cortex, we defined the effects of oxygen and glucose deprivation on NPY expression, using BDNF-induced production of NPY as a functional criterion. NPY neurons exhibited a differential susceptibility to oxygen and glucose deprivation. Although the neurons could withstand oxygen deprivation for 16 hr, they were dramatically damaged by 8 hr of glucose deprivation and by 1-4 hr of deprivation of both oxygen and glucose (N+Glu-). One-hour exposure to N+Glu- led to a transient inhibition ( approximately 50%) of NPY production manifesting within 24 hr and recovering by 5 days thereafter, a 2-hr exposure to N+Glu- led to a sustained inhibition (50-75%) manifesting 1-5 days thereafter, and a 4-hr exposure to N+Glu- led to a total irreversible suppression of BDNF-induced production of NPY manifesting within 24 hr and lasting 8 days after re-supply of oxygen and glucose. Moreover, 1-hr exposure to N+Glu- led to a substantial and 4-hr exposure led to a total disappearance of immunostaining for MAP-2 and NPY but not for GFAP; indicating that neurons are the primary cell-type damaged by oxygen-glucose deprivation. Analysis of cell viability (LDH, MTT) indicated that progressive changes in cell integrity take place during the 4-hr exposure to N+Glu- followed by massive cell death 24 hr thereafter. Thus, we defined a culture system that can serve as a model to study mechanisms by which ischemic insult leads to suppression and eventually death of NPY neurons. Importantly, changes in NPY neurons can be integrated into the overall scheme of ischemic injury in the perinatal brain.

  14. Waste-assimilation study of Koshkonong Creek below sewage-treatment plant at Sun Prairie, Wisconsin

    USGS Publications Warehouse

    Grant, R. Stephen

    1976-01-01

    A waste-load-assimilation study of a reach of Koshkonong Creek below the Sun Prairie, Wisconsin, sewage-treatment-plant outfall indicated that a high level of treatment would be required to meet Wisconsin water-quality standards. To maintain a minimum dissolved-oxygen concentration of 5 mg/liter during the critical summer low-flow period, 5-day carbonaceous biochemical-oxygen demand in waste discharges should not exceed 5 mg/liter and ammonium nitrogen should not exceed 1.5 mg/liter. Advanced treatment with denitrification is required because stream-reaeration coefficients are not high enough to offset deoxygenation caused by an abundance of attached biological slimes. The slimes apparently consumed dissolved oxygen at a rate of about 110 mg/liter per day at the time of the stream survey. During the critical summer low-flow period, natural stream discharge is very small compared to waste-water discharge , so benefits of dilution are insignificant. An evaluation of two proposed alternative waste-water discharge sites indicated that the present discharge site is hydraulically superior to these sites. Stream-reaeration coefficients used in the study were based on measurements using the radioactive-tracer method. (Woodard-USGS)

  15. Trichloroethylene aerobic cometabolism by suspended and immobilized butane-growing microbial consortia: a kinetic study.

    PubMed

    Frascari, Dario; Zanaroli, Giulio; Bucchi, Giacomo; Rosato, Antonella; Tavanaie, Nasrin; Fraraccio, Serena; Pinelli, Davide; Fava, Fabio

    2013-09-01

    A kinetic study of butane uptake and trichloroethylene (TCE) aerobic cometabolism was conducted by two suspended-cell (15 and 30°C) and two attached-cell (15 and 30°C) consortia obtained from the indigenous biomass of a TCE-contaminated aquifer. The shift from suspended to attached cells resulted in an increase of butane (15 and 30°C) and TCE (15°C) biodegradation rates, and a significant decrease of butane inhibition on TCE biodegradation. The TCE 15°C maximum specific biodegradation rate was equal to 0.011 mg(TCE ) mg(protein)(-1) d(-1) with suspended cells and 0.021 mg(TCE) mg(protein)(-1) d(-1) with attached cells. The type of mutual butane/TCE inhibition depended on temperature and biomass conditions. On the basis of a continuous-flow simulation, a packed-bed PFR inoculated with the 15 or 30°C attached-cell consortium could attain a 99.96% conversion of the studied site's average TCE concentration with a 0.4-0.5-day hydraulic residence time, with a low effect of temperature on the TCE degradation performances.

  16. Statistical study of seismo-electromagnetic perturbations observed by the DEMETER wave instruments

    NASA Astrophysics Data System (ADS)

    Pisa, David; Santolik, Ondrej; Parrot, Michel

    We present a statistical study of electromagnetic perturbations in the upper ionosphere observed by the DEMETER satellite (launched in 2004, altitude of orbit about 660 km, still operating). Data intervals measured within 330 km from large (M¿=5.0) surface (depth¡40 km) earthquakes are analyzed. Time intervals spanning from 5 days before to 3 days after the main shock are checked for the presence of seismo-electromagnetic effects, while the other data from the same geographical location are used in order to estimate the common, seismically unperturbed, background. Previous results in the VLF range (20 Hz -18 kHz) have shown that there is a statistically significant decrease of wave intensity shortly (less than 4 hours) before the time of the main shock. In this study all the available DEMETER data are used and all the frequency range from ULF to HF (DC -3.175 MHz) is covered. Various types of electromagnetic waves that could be responsible for this effect are discussed, as well as its dependence on the focal mechanism of an imminent earthquake.

  17. Aspartame and seizure susceptibility: results of a clinical study in reportedly sensitive individuals.

    PubMed

    Rowan, A J; Shaywitz, B A; Tuchman, L; French, J A; Luciano, D; Sullivan, C M

    1995-03-01

    The high intensity sweetener aspartame has been implicated anecdotally in seizure provocation. This possibility was investigated with a randomized, double-blind, placebo-controlled, cross-over study. After an extensive search, 18 individuals (16 adults and 2 children) who had seizures allegedly related to aspartame consumption were admitted to adult or pediatric epilepsy monitoring units where their EEG was monitored continuously for 5 days. Aspartame (50 mg/kg) or identically enpackaged placebo was administered in divided doses at 0800, 1000, and 1200 h on study days 2 and 4. All meals were uniformly standardized on treatment days. No clinical seizures or other adverse experiences were observed after aspartame ingestion. Mean plasma phenylalanine (Phe) concentrations increased significantly after aspartame ingestion (83.6 microM) as compared with placebo (52.3 microM). Results suggest that aspartame, in acute dosage of approximately 50 mg/kg, is no more likely than placebo to cause seizures in individuals who reported that their seizures were provoked by aspartame consumption.

  18. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia

    PubMed Central

    O'Brien, Susan; Jorgensen, Jeffrey; Pierce, Sherry; Faderl, Stefan; Ferrajoli, Alessandra; Koller, Charles; Challagundla, Pramoda; York, Sergernne; Brandt, Mark; Luthra, Rajyalakshmi; Burger, Jan; Thomas, Deborah; Keating, Michael; Kantarjian, Hagop

    2011-01-01

    We conducted this study to determine the feasibility and safety of cladribine followed by rituximab in patients with hairy cell leukemia including the vari-ant form (HCLv). Cladribine 5.6 mg/m2 given IV over 2 hours daily for 5 days was followed ∼ 1 month later with rituximab 375 mg/m2 IV weekly for 8 weeks. Responses were recorded and BM minimal residual disease (MRD) was evaluated after the completion of rituximab. Thirty-six patients have been treated including 5 with HCLv. Median age was 57 years (range, 37-89). All patients (100%) have achieved complete response (CR), defined as presence of no hairy cells in BM and blood with normalization of counts (absolute neutrophil count [ANC]> 1.5 × 109/L, hemoglobin [Hgb] > 12.0 g/dL, platelets [PLT] > 100 × 109/L), as well as resolution of splenomegaly. There were no grade 3 or 4 nonhematologic adverse events directly related to the treatment. Only 1 patient (with HCLv) has relapsed; median CR duration has not been reached (range,1+-63+ months). Three patients with HCLv died including 1 with relapsed disease and 2 from unrelated malignancies. Median survival duration has not been reached (range, 2+-64+ months). Treatment with clad-ribine followed by rituximab is effective tk;4and may increase CR rate. This study was registered at www.clinicaltrials.gov as NCT00412594. PMID:21821712

  19. Investigating reinforcer magnitude and reinforcer delay: a contingency management analog study.

    PubMed

    Packer, Robert R; Howell, Donelle N; McPherson, Sterling; Roll, John M

    2012-08-01

    The influence of reinforcer magnitude and reinforcer delay on smoking abstinence was studied using an analog model of contingency management. Participants (N = 103, 74% men) visited our laboratory 3 times daily for 5 days and received money for providing a breath sample that indicated smoking abstinence (carbon monoxide level ≤6 parts per million). Using a factorial design, we assigned participants randomly to 1 of 4 groups that could earn a total of either $207.50 (high-magnitude condition) or $70.00 (low-magnitude condition), and received earnings either at each visit (no-delay condition) or in a single lump sum 1 week following the study (delay condition). High-magnitude reinforcement, regardless of delay, was associated with higher rates of abstinence than was low-magnitude reinforcement. High magnitude of reinforcement provided immediately but in incremental amounts was associated with longer intervals to relapse during treatment in comparison with high-magnitude reinforcement provided in a single lump sum after a delay. Low rates of responding in the low-magnitude conditions made interpretation of the impact of delay in those conditions difficult. These findings further demonstrate that high magnitude of reinforcement results in better outcomes than does low magnitude of reinforcement, and that a delay to reinforcement can be detrimental-even when a high magnitude of reinforcement is provided.

  20. Chemotherapy-induced nausea and vomiting in breast cancer patients: a prospective observational study.

    PubMed

    Booth, Christopher M; Clemons, Mark; Dranitsaris, George; Joy, Anil; Young, Scott; Callaghan, Walter; Trudeau, Maureen; Petrella, Teresa

    2007-09-01

    Despite advances in the prevention and treatment of emesis, nausea and vomiting are still considered by patients to be among the most severe and feared adverse effects of chemotherapy for breast cancer. There is, however, a paucity of prospective data documenting the prevalence and severity of emesis in patients with breast cancer in the era of modern antiemetics. This prospective multicenter study evaluated chemotherapy-induced nausea and vomiting (CINV) in patients with breast cancer. Patients were given a daily diary to record the frequency and severity of nausea and vomiting during the first 5 days following chemotherapy. Data were collected until either the cessation of chemotherapy or the administration of a maximum of 6 cycles of treatment. Data are available from 143 patients who received a total of 766 cycles of chemotherapy. Prevalence rates of any nausea or any vomiting were, respectively, 37% and 13% at 24 hours and 70% and 15% during days 2-5. Severe emesis was reported by fewer than 10% of patients. Risk factors associated with CINV included age younger than 40 years, nausea expectation, not eating before treatment, and low alcohol use. The prevalence of severe CINV for breast cancer was relatively low compared with the prevalence reported in the literature. As a result of the observational design of this study, the results may better reflect the "true" prevalence of nausea and vomiting than do estimates from previously reported randomized controlled trials. Several patient characteristics that predict which patients are at increased risk of developing severe symptoms were identified.

  1. Fundamental study on the influence of Fusarium infection on quality and ultrastructure of barley malt.

    PubMed

    Oliveira, Pedro M; Mauch, Alexander; Jacob, Fritz; Waters, Deborah M; Arendt, Elke K

    2012-05-01

    Barley infection with Fusarium species has been a long standing problem for the malting and brewing industries. In this study, we evaluate the impact of Fusarium culmorum infected raw barley on the final malt quality. Barley grains were infected for 5 days at optimum fungal growth conditions. Grains were fully characterized and compared to standard barley grains. Due to fungal infection, germinative energy of infected barley grains decreased by 45%; its water sensitivity increased dramatically, and grains accumulated 199 μg/kg of deoxynivalenol (DON). Barley grains were subsequently malted for 8 days, fully characterized and compared to standard malt grains. Fungal growth behavior was evaluated during malting using a PCR-based assay and mycotoxins were measured using HPLC. Fungal biomass increased in grains, during all stages of malting. Infected malt accumulated 8-times its DON concentration during malting. Kernel ultrastructure was evaluated using scanning electron and confocal laser scanning microscopy. Infected malt grains were characterized by extreme structural proteolytic, (hemi)-cellulolytic and starch deterioration with increased friability and fragmentation. Infected grains had higher protease and β-glucanase activities, lower amylase activity, a greater proportion of free amino and soluble nitrogen, and a lower β-glucan content. Malt loss was over 27% higher in infected malt in comparison to the control. The results of this study revealed that 20% F. culmorum infected barley kernels lead to a significant reduction in malt quality as well as mycotoxin formation.

  2. Pathologic studies of acute rejection of mismatched feline musculocutaneous flaps. Effect of cyclosporine and prednisolone.

    PubMed

    Gregory, C R; Gourley, I M; Ferreira, H; Moore, P F; Imondi, K A; Patz, J D; Gregory, T A; Pedersen, N C

    1991-06-01

    The gracilis musculocutaneous flap was developed as an allograft model to study acute rejection and immunosuppression in the cat. Twelve adult cats received a MLC incompatible flap. Six of the cats received cyclosporine oral solution and prednisolone (0.5 mg/kg/24 hr) for 100 days and six cats were not treated. Trough whole-blood levels of cyclosporine in the treatment group were maintained at approximately 750 ng/ml for 70 days, then 500 ng/ml for the remaining 30 days. Three flaps failed due to technical problems; 5 flaps were studied in the treatment group and 4 in the untreated group. All 5 flaps in the treatment group survived the 100 day treatment period and were rejected 30 +/- 26 days following cessation of treatment. Prior to discontinuation of treatment, with the exception of one cat, inflammatory changes associated with rejection were not observed in biopsy specimen. The flaps in the untreated group survived 13 +/- 1.5 days. Histopathologic examination of the flaps revealed little difference in the appearance of acute rejection and rejection after cessation of therapy. The most prominent lesion was a vasculitis with extensive perivascular lymphohistocytic inflammation. The lymphoid infiltrates consisted predominantly of T cells of both major classes (CD4 and CD8). Full-thickness epidermal necrosis and subsequent bacterial invasion followed vascular compromise.

  3. Montelukast is as effective as penicillin in treatment of acute otitis media: An experimental rat study

    PubMed Central

    Uçar, Seçil; Huseynov, Tural; Çoban, Melahat; Sarıoğlu, Sülen; Şerbetçioğlu, Bülent; Yalcin, Arzu Didem

    2013-01-01

    Background Leukotrienes are the major factors in the formation of edema and mucus, as well as development of tuba Eustachii dysfunction in acute otitis media. We developed an experimental acute suppurative otitis media model and compared the responses of rats to penicillin and combinations of leukotriene antagonist with respect to histopathological observations conducted in early and late phases. Material/Methods A total of 83 ears from 56 Wistar rats were used in this study. Pneumococcus suspension was injected trans-tympanically into all rats. Subjects were classified into 4 different groups with 14 rats in each. In Group A, intramuscular penicillin G was injected for a period of 5 days. In Group B, intraperitoneal montelukast was injected for 21 days in addition to penicillin. In Group C, intraperitoneal montelukast isotonic NaCl in Group D was injected into rats for 21 days. Results No significant difference was found between the groups, except for mucosal vascularization with respect to mucosal and TM parameters in early phases. Furthermore, considerable deviations were observed for the recuperation of TM and mucosal inflammation for groups in which subjects were injected with montelukast as compared to other groups of the study in the late phases. Conclusions When the parameters of inflammation in the rat middle ear were compared with each other, most of these parameters did not show any statistically significant beneficial effects in montelukast and penicillin groups. PMID:24048018

  4. The health effects of swimming at Sydney beaches. The Sydney Beach Users Study Advisory Group.

    PubMed Central

    Corbett, S J; Rubin, G L; Curry, G K; Kleinbaum, D G

    1993-01-01

    OBJECTIVES. The purpose of the study was to determine the health risks of swimming at ocean beaches in Sydney, Australia. METHODS. From people attending 12 Sydney beaches in the period from December 5, 1989 to February 26, 1990, we recruited a cohort of 8413 adults who agreed to participate in this study. Of these, 4424 were excluded either because they had been swimming in the previous 5 days or because they reported a current illness. Of the remainder, 2839 successfully completed a follow-up telephone interview conducted within 10 days after recruitment. We recorded reported respiratory, gastrointestinal, eye, and ear symptoms and fever that occurred within the 10 days between initial interview on the beach and the follow-up interview. RESULTS. A total of 683 participants (24.0%) reported experiencing symptoms in the 10 days following initial interview. Of these, 435 (63.7%) reported respiratory symptoms. Swimmers were almost twice as likely as nonswimmers to report symptoms. There was a linear relationship between water pollution and all reported symptoms with the exception of gastrointestinal complaints. CONCLUSIONS. Swimmers at Sydney ocean beaches are more likely to report respiratory, ear, and eye symptoms than beachgoers who do not swim. The incidence of these symptoms increases slightly with increasing levels of pollution. PMID:8259798

  5. Development of an orange juice surrogate for the study of dental erosion.

    PubMed

    Scaramucci, Tais; Hara, Anderson T; Zero, Domenick T; Ferreira, Stella S; Aoki, Idalina V; Sobral, Maria Angela P

    2011-01-01

    The aim of this study was to create a synthetic juice (SJ) to be used as a surrogate for natural orange juices in erosion studies, verifying its erosive potential. The SJ was formulated based on the chemical composition of orange juices from different locations. Forty enamel and 40 root dentin specimens were randomly assigned into 4 experimental groups (n = 10): SJ; 1% Citric Acid (CA); Minute Maid Original® (MM) and Florida Natural Original® (FN). The specimens were immersed in their respective solutions for 5 min, 6x/day for 5 days, in an erosion-remineralization cycling model. Enamel specimens were analyzed by surface Knoop microhardness and optical profilometry and dentin specimens only by optical profilometry. Outcomes were analyzed statistically by ANOVA followed by Tukey's test considering a significance level of 5%. For enamel, the surface loss and microhardness changes found for MM and SJ groups were similar (p>0.05) and significantly lower (p<0.01) than those found in the CA group. For dentin, CA promoted significantly greater (p<0.01) surface loss compared with all the other groups. No significant difference (p>0.05) was observed in dentin surface loss between MM and SJ. In conclusion, CA was the most erosive solution, and SJ had a similar erosive potential to that of MM natural orange juice.

  6. Evaluation of Eslicarbazepine acetate on cardiac repolarization in a thorough QT/QTc study.

    PubMed

    Vaz-Da-Silva, Manuel; Nunes, Teresa; Almeida, Luis; Gutierrez, Maria J; Litwin, Jeffrey S; Soares-Da-Silva, Patrício

    2012-02-01

    This study investigated the effect of eslicarbazepine acetate (ESL) on cardiac repolarization in healthy adult volunteers. A randomized, placebo/active-controlled, 4-period crossover study was conducted in 67 participants. In 3 periods, participants received once-daily doses of ESL 1200 mg, ESL 2400 mg, and placebo for 5 days; in 1 period, participants received placebo on days 1 to 4 and a 400-mg moxifloxacin single dose on day 5. In each period, 24-hour 12-lead Holter monitoring was performed on days -;1 (baseline) and 5. There was no clinically relevant effect of ESL 1200 mg and 2400 mg versus placebo on cardiac depolarization or repolarization as measured by the QRS or QTc intervals, respectively. Mean PR interval increased following ESL 1200 mg and 2400 mg, but there was no participant with a PR interval above the upper limit of the normal range (200 ms). The upper bound of the 95% confidence interval for the placebo-corrected change from baseline of the individually corrected QT interval (QTcI) following administration of ESL 1200 mg and ESL 2400 mg was <10 ms at every time point. Moxifloxacin caused an increase in QTcI above the 10-ms threshold for clinical significance at several time points, demonstrating assay sensitivity. It is concluded that administration of ESL 1200 mg and ESL 2400 mg did not induce a clinically significant prolongation of the QTcI interval.

  7. Office Hysteroscopic Laser Enucleation of Submucous Myomas without Mass Extraction: A Case Series Study

    PubMed Central

    Haimovich, Sergio; López-Yarto, Maite; Urresta Ávila, Julio; Saavedra Tascón, Alejandro; Hernández, José L.; Carreras Collado, Ramón

    2015-01-01

    Background and Objectives. A new two-step hysteroscopic myomectomy carried out in the office setting and without anesthesia was feasible for the excision of submucous myomas. The objective of this study was to assess whether removal of submucous myomas from the uterine cavity after hysteroscopic laser enucleation is necessary. Methods. Between June 2009 and April 2013, all outpatients with symptomatic myomatosis (bleeding, pelvic pain, and infertility) assessed ultrasonographically were eligible to participate in a prospective study. All patients underwent office hysteroscopic enucleation of submucous myomas. Enucleated myomas were left in the uterine cavity. Neither anesthesia nor antibiotic prophylaxis was used. Results. Sixty-one women (mean age: 47.3 years) were included. Regardless of hysteroscopic localization and grading, all myomas were enucleated. The mean (standard deviation, SD) diameter of the myoma as measured by the ultrasound scan was 22.6 (8.5) mm. In 29 cases (47.5%), the diameter of the resected myoma was >20 mm and in 10 cases (16.4%) >30 mm. After a mean follow-up of 68.2 (16.5) days, none of the patients showed a residual myoma inside the uterine cavity. Conclusions. The present results indicate that leaving laser-enucleated submucous myoma in the uterine cavity is a feasible and safe therapeutic option. PMID:26090457

  8. Confirmation studies of Soviet research on immunological effects of microwaves: Russian immunology results.

    PubMed

    Grigoriev, Yury G; Grigoriev, Oleg A; Ivanov, Alexander A; Lyaginskaya, Antonina M; Merkulov, Anton V; Shagina, Natalia B; Maltsev, Vyacheslav N; Lévêque, Philippe; Ulanova, Alla M; Osipov, Vyacheslav A; Shafirkin, Alexander V

    2010-12-01

    This paper presents the results of a replication study performed to investigate earlier Soviet studies conducted between 1974 and 1991 that showed immunological and reproductive effects of long-term low-level exposure of rats to radiofrequency (RF) electromagnetic fields. The early studies were used, in part, for developing exposure standards for the USSR population and thus it was necessary to confirm the Russian findings. In the present study, the conditions of RF exposure were made as similar as possible to those in the earlier experiments: Wistar rats were exposed in the far field to 2450 MHz continuous wave RF fields with an incident power density in the cages of 5 W/m² for 7 h/day, 5 days/week for a total of 30 days, resulting in a whole-body SAR of 0.16 W/kg. Effects of the exposure on immunological parameters in the brain and liver of rats were evaluated using the complement fixation test (CFT), as in the original studies, and an additional test, the more modern ELISA test. Our results, using CFT and ELISA, partly confirmed the findings of the early studies and indicated possible effects from non-thermal RF exposure on autoimmune processes. The RF exposure resulted in minor increases in formation of antibodies in brain tissue extract and the exposure did not appear to be pathological. In addition, a study was conducted to replicate a previous Soviet study on effects from the injection of blood serum from RF-exposed rats on pregnancy and foetal and offspring development of rats, using a similar animal model and protocol. Our results showed the same general trends as the earlier study, suggesting possible adverse effects of the blood serum from exposed rats on pregnancy and foetal development of intact rats, however, application of these results in developing exposure standards is limited.

  9. Aerosal studies

    NASA Technical Reports Server (NTRS)

    Harris, F. S., Jr.

    1976-01-01

    Various methods of measuring aerosols were studied in terms of the best methods to use, the instruments or techniques actually employed, and those techniques applied in field measurements on air quality as influenced by rocket launch effluents, and in an urban environment. Further studies were initiated on the remote sensing of aerosols by satellites and the influence of aerosols on visibility. The characterization of aerosols by measurement of scattered light was studied on Mie theory calculations.

  10. Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study.

    PubMed

    Amichai, B; Nitzan, B; Mosckovitz, R; Shemer, A

    2010-01-01

    Background Onychomycosis is a common disease; topical treatment is usually poorly effective, while systemic treatment is more effective but may be associated with side-effects. Iontophoretic drug delivery may improve drug penetration through the nail and lead to better therapeutic results. Objectives To evaluate the efficacy, safety and tolerability of topical treatments with terbinafine HCl delivered with or without an iontophoretic patch in patients with onychomycosis of the toenails. Methods Patients enrolled into the study were divided randomly into two groups. Group A was treated with terbinafine and an iontophoretic patch (at a constant current density of 100 microA cm(-2)). Group B was treated with terbinafine without iontophoresis. Treatment was overnight wear, every day, 5 days per week, for 4 weeks. Follow-up period was 8 weeks from the end of treatment. Results A significant clinical response was recorded in patients of group A (active group). The percentage of patients having healthy toenail growth of more than 1.5 mm at the end of treatment was 40% compared with 11% in patients treated with terbinafine without current (passive group). The percentage of patients having fungal elements (KOH) in nail specimens decreased significantly at 8 weeks following the completion of treatment: 16% in the active group vs. 53% in the passive group. Patients in the active group reported a tingling sensation that is expected when using an iontophoretic drug delivery treatment. Conclusions The delivery of terbinafine under an electrical current of 100 microA cm(-2) appears to be efficacious and safe and is well tolerated for the treatment of nail onychomycosis.

  11. Evaluation of chikungunya virus infection in children from India during 2009-2010: A cross sectional observational study.

    PubMed

    Raghavendhar, B Siva; Ray, Pratima; Ratagiri, Vinod H; Sharma, B S; Kabra, Sushil K; Lodha, Rakesh

    2016-06-01

    Chikungunya virus, a small (about 60-70 nm diameter), spherical, enveloped, positive, single stranded RNA virus is transmitted by Aedes mosquitoes. After a short period of incubation (3-5 days) symptoms like fever with joint pains and others start appearing. After a gap of 20 years, this virus re-emerged during 2006-2008 in India causing a major outbreak of CHIKV in India. This study was conducted subsequent to the major outbreak in order to evaluate the proportion of chikungunya virus infection in children with suggestive symptoms at three geographical locations of India. Lineage of circulating strains and changes in the E1 structural polypeptide were also determined. Blood samples were collected (in Sodium citrate vacutainer tubes) during 1st June 2009 to 31st May 2010 from children (age 0 ≤ 18 years) suspected to have chikungunya infection, that is, those who presented with sudden onset of fever and/or joint pain, myalgia, and headache from three regions of India, All India Institute of Medical Sciences (AIIMS) in New Delhi, Karnataka Institute of Medical Sciences (KIMS) in Hubli and Sawai Mansingh Medical College (SMS) in Jaipur. Detection of CHIKV antibodies in all acute-phase patient plasma samples was done by IgM ELISA and for samples within ≤5 days of fever, a one-step RT-PCR was carried out on a block thermo-cycler targeting 294 bp region of E1 gene that codes for the viral envelope protein. Comparison of nucleotide and amino acid sequences from few positive samples of two regions was done with African S-27 reference strain using BioEdit. A phylogenetic tree was constructed using MEGA 6 by using the Maximum Likelihood method based on the Kimura 2-parameter model. Out of the 723 acute phase samples tested from three geographical locations of India, Chikungunya virus infection was detected in 249/723 (34.44%) subjects by either IgM Elisa (180/723) or RT-PCR (69/412). RT-PCR was employed in samples collected from children with ≤5 days of fever. Maximum

  12. Inhalation carcinogenicity study with nickel metal powder in Wistar rats

    SciTech Connect

    Oller, Adriana R. Kirkpatrick, Daniel T.; Radovsky, Ann; Bates, Hudson K.

    2008-12-01

    Epidemiological studies of nickel refinery workers have demonstrated an association between increased respiratory cancer risk and exposure to certain nickel compounds (later confirmed in animal studies). However, the lack of an association found in epidemiological analyses for nickel metal remained unconfirmed for lack of robust animal inhalation studies. In the present study, Wistar rats were exposed by whole-body inhalation to 0, 0.1, 0.4, and 1.0 mg Ni/m{sup 3} nickel metal powder (MMAD = 1.8 {mu}m, GSD = 2.4 {mu}m) for 6 h/day, 5 days/week for up to 24 months. A subsequent six-month period without exposures preceded the final euthanasia. High mortality among rats exposed to 1.0 mg Ni/m{sup 3} nickel metal resulted in the earlier termination of exposures in this group. The exposure level of 0.4 mg Ni/m{sup 3} was established as the MTD for the study. Lung alterations associated with nickel metal exposure included alveolar proteinosis, alveolar histiocytosis, chronic inflammation, and bronchiolar-alveolar hyperplasia. No increased incidence of neoplasm of the respiratory tract was observed. Adrenal gland pheochromocytomas (benign and malignant) in males and combined cortical adenomas/carcinomas in females were induced in a dose-dependent manner by the nickel metal exposure. The incidence of pheochromocytomas was statistically increased in the 0.4 mg Ni/m{sup 3} male group. Pheochromocytomas appear to be secondary to the lung toxicity associated with the exposure rather than being related to a direct nickel effect on the adrenal glands. The incidence of cortical tumors among 0.4 mg Ni/m{sup 3} females, although statistically higher compared to the concurrent controls, falls within the historical control range; therefore, in the present study, this tumor is of uncertain relationship to nickel metal exposure. The lack of respiratory tumors in the present animal study is consistent with the findings of the epidemiological studies.

  13. Studying Zooarchaeology

    ERIC Educational Resources Information Center

    Moore, Molly; Wolf, Deborah; Butler, Virginia L.

    2012-01-01

    Children often associate the study of bones with dinosaurs or crime scenes. This unit introduces students to "zooarchaeology," the study of animal remains from archaeological sites. Students in grades 3-5 engage in hands-on activities examining bones, shells, and other "hard parts" of animals. They use their observations as a starting point for…

  14. Study Carrels

    ERIC Educational Resources Information Center

    Training, 1977

    1977-01-01

    Information on various study carrels to provide individualized learning space for training use is presented. It is noted that carrels may be standard models or customized, and most are wired for audiovisual equipment. A list of study carrel suppliers and manufacturers is included. (MF)

  15. Stream Studies.

    ERIC Educational Resources Information Center

    Hamilton City Board of Education (Ontario).

    This manual provides teachers with some knowledge of ecological study methods and techniques used in collecting data when plants and animals are studied in the field. Most activities deal with the interrelatedness of plant and animal life to the structure and characteristics of a stream and pond. Also included in this unit plan designed for the…

  16. Bird Study

    ERIC Educational Resources Information Center

    Katz, Margaret

    1978-01-01

    Excerpts from a first grade teacher's diary describe bird study activities done by the class over a two week period. Each student studied a bird of their choice in detail and made a papier-mache model of the bird. These models were exhibited at a student initiated program for visitors. (MA)

  17. Women's Studies.

    ERIC Educational Resources Information Center

    Davis, James E., Ed.; Davis, Hazel K., Ed.

    1981-01-01

    The 16 articles in this journal issue deal with women's studies within the English curriculum. Topics discussed in the articles include (1) the feminist challenge to the male-centered curriculum in higher education; (2) the women's movement and women's studies; (3) connotations of the word "girl"; (4) women in English education; (5) the new…

  18. Social Studies.

    ERIC Educational Resources Information Center

    White, Cam, Ed.

    This document contains the following papers on social studies instruction and technology: (1) "Waking the Sleeping Giant: Social Studies Teacher Educators Collaborate To Integrate Technology into Methods' Courses" (Cheryl Mason, Marsha Alibrandi, Michael Berson, Kara Dawson, Rich Diem, Tony Dralle, David Hicks, Tim Keiper, and John Lee);…

  19. A comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced memory impairments in rats

    PubMed Central

    Jawaid, Talha; Jahan, Shah; Kamal, Mehnaz

    2015-01-01

    The comparative study of neuroprotective effect of angiotensin converting enzyme inhibitors against scopolamine-induced neuroinflammation in albino Wistar rats was studied. Male albino rats were administered with scopolamine to induce memory impairment. The standard nootropic agent, piracetam (200 mg/kg b.w., [i.p.]), perindopril (0.1 mg/kg b.w., [i.p.]), enalapril (0.1 mg/kg b.w., [i.p.]), and ramipril (0.1 mg/kg b.w., [i.p.]) were administered in different group of animals for 5 days. On 5th day, scopolamine (1 mg/kg b.w., i.p.) was administered after 60 min of the last dose of test drug. Memory function was evaluated in Morris water maze (MWM) test and pole climbing test (PCT). Biochemical estimations like glutathione (GSH), malondialdehyde (MDA), and acetylcholinesterase activity in the brain were estimated after completion of behavior study. All three test groups shows improvement in learning and memory in comparison to control group. Perindopril treated group showed a more effective significant decrease in escape latency time and transfer latency time compared to enalapril and ramipril treated group on day 4 in MWM test and PCT, respectively. Perindopril shows a significant reduction in MDA level and acetylcholinesterase activity and a significant rise in GSH level compared to enalapril and ramipril. The finding of this study indicates that Perindopril is more effective in memory retention compared to enalapril and ramipril. PMID:26317078

  20. Electromyogram-controlled assistive exercise for the motor recovery of shoulder in chronic hemiplegia: A pilot study.

    PubMed

    Park, Byung Kyu; Kim, Ji-Won; Kwon, Yuri; Heo, Jae-Hoon; Yoon, Joo-Seok; Eom, Gwang-Moon

    2015-01-01

    Correct-active-repetitive exercise is important for the motor recovery in hemiplegics. The present study hypothesizes that the electromyogram (EMG)-controlled assistance of motion would be an effective implementation of the concept for the rehabilitation of the hemiplegic shoulder, even in chronic patients. This study aims to investigate the feasibility of the suggested method. The motor intention is derived from the EMG of the shoulder muscles and the shoulder movement (flexion and abduction) is assisted by an electro-mechanical system only when the motor intention (EMG amplitude) exceeded the threshold. Twelve patients in the chronic stage of stroke participated in this pilot study. The EMG-controlled assistive exercise lasts for two weeks, 20 min per day and 5 days a week. The active range of motion in both abduction and flexion increases significantly after the intervention (p < 0.01). The maximum torque increases in both directions, and the increase is significant in the abduction (p < 0.01). The Fugl-Myer motor assessment score is improved greatly in the shoulder-related items (p < 0.01), but neither in the shoulder-unrelated items of the upper extremity (p = 0.13) nor in the lower extremity items (p = 0.19). This pilot study demonstrates that EMG-controlled assistive exercise can improve shoulder motor functions related to selected muscles and the suggested method is promising for the motor recovery of the shoulder in chronic hemiplegia.

  1. Toxicology and Carcinogenesis Studies of Furfuryl Alcohol (CAS No. 98-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

    PubMed

    1999-02-01

    Furfuryl alcohol-based resins are used as binding agents in foundry sand and as corrosion inhibitors in mortar, grout, and cement. Because of their heat resistance, furan resins are used in the manufacture of fiberglass-reinforced plastic equipment. Furfuryl alcohol was selected for evaluation because of the absence of data on its carcinogenic potential and its large production volume, widespread use in manufacturing, and ubiquitous presence in consumer goods. Male and female F344/N rats and B6C3F1 mice were exposed to furfuryl alcohol (greater than 98% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female rats exposed to 250 ppm died by day 2 of the study, and one male rat exposed to 125 ppm died on day 5. Final mean body weights of male and female rats exposed to 125 ppm were significantly less than those of the chamber control groups. Male rats exposed to 31, 63, or 125 ppm and female rats exposed to 125 ppm gained less weight than the chamber control groups. Clinical findings included dyspnea, hypoactivity, and nasal and ocular discharge in males and females exposed to 63, 125, or 250 ppm. All exposed animals developed lesions in the nasal respiratory epithelium and olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female mice exposed to 250 ppm died by day 4 of the study, and one female mouse exposed to 125 ppm died on day

  2. Culture Studies: Hawaiian Studies Project.

    ERIC Educational Resources Information Center

    Hazama, Dorothy, Ed.

    Reports and materials from the Hawaiian Studies Project are presented. The document, designed for elementary school teachers contains two major sections. The first section describes the planning phase of the project, the Summer Institute for Hawaiian Culture Studies (1976) and the follow-up workshops and consultant help (1976-77). The appendix to…

  3. The radon cycle and its daughters - an application to the study of troposphere-stratosphere exchanges

    NASA Astrophysics Data System (ADS)

    Lambert, G.; Polian, G.; Jegou, A.; Sanak, J.; Ardouin, B.; Buisson, A.; Le Roulley, J. C.

    1982-12-01

    The global activities of the natural radioactive nuclides Rn-222, Pb-210, Bi-210, and Po-210 in the whole atmosphere are studied. A two-box model which assumes the existence of a steady state for the whole atmosphere is employed since the residence times of the aerosols and air masses are different in the troposphere and in the stratosphere. In each reservoir, the production of a nuclide by radioactive decay of its precursor is balanced simultaneously by its own radioactivity, by the flux of atoms transferred to or from the other reservoir, and in the case of the troposphere, by scavenging. The model is used to consider an unknown emanation of Rn-222 from the soil of the continents and also the existence of possible volcanic sources for each nuclide. Among other results, it is found that the Rn-222 emanation rate from the surface of the continents is 0.72 atom/sq cm-sec, and about 2 percent of this flux is able to reach the stratosphere. The scavenging constant of the submicronic aerosols in the troposphere is determined to be 0.00011/min, which corresponds to a mean residence time of 6.5 days in the global troposphere. The flux of air exchanged across the tropopause is determined to be between 4.2-9 x 10 to the 12th kg/min, which corresponds to a mean residence time in the stratosphere between 0.23-0.50 year.

  4. Study on characteristics of biocometabolic removal of omethoate by the Aspergillus spp.

    PubMed

    Chun, Meng; Chngchun, S; Yanghao, Guo; Shi Xian'ai; Jianfeng, Cheng; Fen, Yan

    2004-03-01

    A strain Aspergillus spp. F1 which could effectively metabolized omethoate was screened out in this study. F1 tended to form granula with diameter 4-5mm after 5 days culture in shaker. The pH range from 4.5 to 6.5 was the suitable pH range for growth and metabolism of Aspergillus spp. F1. The maximum omethoate removal rate was about 3.0mg/(hL), and the removal fraction of omethoate reached 90% after 8 days culture when initial concentrations of omethoate were not more than 2000mg/L in medium. There was no obvious relativity between cell growth and cometabolism of omethoate. Starch was the best carbon source for omethoate removal and the result after 3 days reached 56.6% removal. F1 could use omethoate to metabolize as single nitrogen or phosphate source. The residual fragments in medium after treatment with the Aspergillus spp. F1 were determined by gas chromatography-mass spectrometry. The analysis results showed that only fragment o,o,s,-trimethyl phosphorothioate (TEP) containing phosphorus was available and the fragment containing nitrogen was consumed by F1 thoroughly in culture process. But no accumulations of TEP were observed in the omethoate bioremediation process. F1 could effectively remove omethoate in complex nutritional environment safely.

  5. Thermally reduced graphene oxide: The study and use for reagentless amperometric D-fructose biosensors.

    PubMed

    Šakinytė, Ieva; Barkauskas, Jurgis; Gaidukevič, Justina; Razumienė, Julija

    2015-11-01

    Aiming to create reagentless amperometric D-fructose biosensor, graphene based electrode materials have been synthesized by newly proposed thermal reduction of graphene oxide. The method allowed to separate and collect different fractions of thermally reduced graphene oxide (TRGO) with different physicochemical properties. The structural characteristics and surface morphologies of TRGO fractions were evaluated using SEM, XRD, TGA analysis, Raman spectroscopy and BET measurements. Three different fractions of TRGO were tested as electrode materials for D-fructose amperometric biosensors. The direct electron transfer (DET) from the active site of D-fructose dehydrogenase (FDH) to the electrode was achieved with all TRGO fractions. High values of the sensitivity (up to 14.5 μA mM(-1) cm(-2)) are of the same order as these for other D-fructose sensors based on the synergistic mediated processes. The relationships between the structure of TRGO fractions and the molecular processes determining the effect of DET in bioelectrocatalysis by FDH have been studied. Stability of the D-fructose biosensors was also assessed. The best results were achieved when immobilization of FDH was performed using a crosslinking with glutaraldehyde. For the best group, after a period of 5 days the sensitivity of the biosensor for D-fructose determination decreased by less than 20%.

  6. Patients’ and orthodontists’ perceptions of miniplates used for temporary skeletal anchorage: A prospective study

    PubMed Central

    Cornelis, Marie A.; Scheffler, Nicole R.; Nyssen-Behets, Catherine; De Clerck, Hugo J.; Tulloch, J. F. Camilla

    2009-01-01

    Introduction Temporary skeletal anchorage is a relatively recent addition to orthodontic treatment. Surgical miniplates, modified with intraoral attachments, provide an alternative to miniscrews for skeletal anchorage. In this study, we wanted to determine patients’ and providers’ perceptions of miniplate use during orthodontic treatment. Methods Consecutive patients having miniplates placed as part of their treatment completed questionnaires about their experiences during surgery and orthodontic treatment. A total of 200 miniplates were placed for 97 patients. The 30 orthodontists treating these patients also completed questionnaires concerning miniplate success, handling complexity, and whether these devices simplified treatment. Results The success rate was 92.5%. The devices were well tolerated by the patients. After a year, 72% of the patients reported that they did not mind having the implant, and 82% said that the surgical experience was better than expected, with little or no pain. The most frequent problems were postsurgical swelling, lasting 5 days on average, and cheek irritation experienced initially by more than a third of the patients, but it lessened over time. The clinicians reported that these devices were easy to use and greatly simplified orthodontic treatment. Conclusions Miniplates are well accepted by patients and providers and are a safe and effective adjunct for complex orthodontic treatments. PMID:18174066

  7. Testing global positioning system telemetry to study wolf predation on deer fawns

    USGS Publications Warehouse

    Demma, D.J.; Barber-Meyer, S. M.; Mech, L.D.

    2007-01-01

    We conducted a pilot study to test the usefulness of Global Positioning System (GPS) collars for investigating wolf (Canis lupus) predation on white-tailed deer (Odocoileus virginianus) fawns. Using GPS collars with short location-attempt intervals on 5 wolves and 5 deer during summers 2002-2004 in northeastern Minnesota, USA, demonstrated how this approach could provide new insights into wolf hunting behavior of fawns. For example, a wolf traveled ???1.5-3.0 km and spent 20-22 hours in the immediate vicinity of known fawn kill sites and ???0.7 km and 8.3 hours at scavenging sites. Wolf travel paths indicated that wolves intentionally traveled into deer summer ranges, traveled ???0.7-4.2 km in such ranges, and spent <1-22 hours per visit. Each pair of 3 GPS-collared wolf pack members were located together for ???6% of potential locations. From GPS collar data, we estimated that each deer summer range in a pack territory containing 5 wolves ???1 year old and hunting individually would be visited by a wolf on average every 3-5 days. This approach holds great potential for investigating summer hunting behavior of wolves in areas where direct observation is impractical or impossible.

  8. WRF-model data assimilation studies of landfalling atmospheric rivers and orographic precipitation over Northern California

    NASA Astrophysics Data System (ADS)

    Eiserloh, Arthur J., Jr.

    In this study, data assimilation methods of 3-D variational analysis (3DVAR), observation nudging, and analysis (grid) nudging were evaluated in the Weather Research and Forecasting (WRF) model for a high-impact, multi-episode landfalling atmospheric river (AR) event for Northern California from 28 November to 3 December, 2012. Eight experiments were designed to explore various combinations of the data assimilation methods and different initial conditions. The short-to-medium range quantitative precipitation forecast (QPF) performances were tested for each experiment. Surface observations from the National Oceanic and Atmospheric Administration's (NOAA) Hydrometeorology Network (HMT), National Weather Service (NWS) radiosondes, and GPS Radio Occultation (RO) vertical profiles from the Constellation Observing System for Meteorology Ionosphere and Climate (COSMIC) satellites were used for assimilation. Model results 2.5 days into the forecast showed slower timing of the 2nd AR episode by a few hours and an underestimation in AR strength. For the entire event forecasts, the non-grid-nudging experiments showed the lowest mean absolute error (MAE) for rainfall accumulations, especially those with 3DVAR. Higher-resolution initial conditions showed more realistic coastal QPFs. Also, a 3-h nudging time interval and time window for observation nudging and 3DVAR, respectively, may be too large for this type of event, and it did not show skill until 60-66 h into the forecast.

  9. Ganoderma neo-japonicum Imazeki revisited: Domestication study and antioxidant properties of its basidiocarps and mycelia

    PubMed Central

    Tan, Wee-Cheat; Kuppusamy, Umah Rani; Phan, Chia-Wei; Tan, Yee-Shin; Raman, Jegadeesh; Anuar, Azliza Mad; Sabaratnam, Vikineswary

    2015-01-01

    Mushroom cultivation benefits humankind as it deliberately encourages wild mushrooms to be commercially propagated while recycling agricultural wastes. Ganoderma neo-japonicum is a rare polypore mushroom found growing on decaying Schizostachyum brachycladium (a tropical bamboo) clumps in Malaysia. The Malaysian indigenous tribes including the Temuans and Temiars use the basidiocarps of G. neo-japonicum to treat various ailments including diabetes. In this study, the domestication of G. neo-japonicum in artificial logs of different agricultural residues was investigated. Sawdust promoted the mycelia spawn colonisation in the shortest period of 38 ± 0.5 days. However, only sawdust and bamboo dust supported the primodia formation. Complex medium supported mycelium growth in submerged cultures and 27.11 ± 0.43 g/L of mycelia was obtained after 2 weeks of cultivation at 28 °C and 200 rpm. Antioxidant potential in mushroom may be influenced by different cultivation and extraction methods. The different extracts from the wild and cultivated basidiocarps as well as mycelia were then tested for their antioxidant properties. Aqueous and ethanol extracts of mycelia and basidiocarps tested had varying levels of antioxidant activities. To conclude, domestication of wild G. neo-japonicum using agroresidues may ensure a continuous supply of G. neo-japonicum for its medicinal use while ensuring the conservation of this rare species. PMID:26213331

  10. Photodynamic therapy of locally advanced pancreatic cancer (VERTPAC study): final clinical results

    NASA Astrophysics Data System (ADS)

    Huggett, M. T.; Jermyn, M.; Gillams, A.; Mosse, S.; Kent, E.; Bown, S. G.; Hasan, T.; Pogue, B. W.; Pereira, S. P.

    2013-03-01

    We undertook a phase I dose-escalation study of verteporfin photodynamic therapy (PDT) in 15 patients with locally advanced pancreatic cancer. Needle placement and laser delivery were technically successful in all patients. Thirteen patients were treated with a single laser fibre. Three treatments were carried out each at 5, 10 and 20 J/cm2; and 5 treatments (4 patients) at 40 J/cm2. A further 2 patients were treated with 2 or 3 laser fibres at 40 J/cm2. Tumour necrosis was measured on CT (computed tomography) by two radiologists 5 days after treatment. There was a clear dosedependent increase in necrosis with a median area of 20 x 16 mm (range 18 x 16 to 35 x 30 mm) at 40 J/cm2. In the 2 patients treated with multiple fibres, necrosis was 40 x 36 mm and 30 x 28 mm, respectively. There were no early complications in patients treated with a single fibre. Both patients treated with multiple fibres had evidence on CT of inflammatory change occurring anterior to the pancreas but without clinical deterioration. These results suggest that single fibre verteporfin PDT is safe in a clinical setting up to 40J/cm2 and produces a dose-dependent area of pancreatic necrosis.

  11. A safety and tolerability study of differently-charged nanoparticles for local pulmonary drug delivery

    SciTech Connect

    Harush-Frenkel, Oshrat; Bivas-Benita, Maytal; Nassar, Taher; Springer, Chaim; Sherman, Yoav; Avital, Avraham; Altschuler, Yoram; Borlak, Jurgen; Benita, Simon

    2010-07-15

    Nanoparticle (NP) based drug delivery systems provide promising opportunities in the treatment of lung diseases. Here we examined the safety and tolerability of pulmonary delivered NPs consisting of PEG-PLA as a function of particle surface charge. The rationale for such a comparison should be attributed to the differential pulmonary toxicity of positively and negatively charged PEG-PLA NP. Thus, the local and systemic effects of pulmonary administered NPs were investigated following 5 days of daily endotracheal instillation to BALB/c mice that were euthanized on the eighth or nineteenth day of the experiment. We collected bronchoalveolar lavages and studied hematological as well as histochemistry parameters. Notably, the cationic stearylamine based PEG-PLA NPs elicited increased local and systemic toxic effects both on the eighth and nineteenth day. In contrast, anionic NPs of similar size were much better tolerated with local inflammatory effects observed only on the eighth experimental day after pulmonary instillation. No systemic toxicity effect was observed although a moderate change was noted in the platelet count that was not considered to be of clinical significance. No pathological observations were detected in the internal organs following instillation of anionic NPs. Overall these observations suggest that anionic PEG-PLA NPs are useful pulmonary drug carriers that should be considered as a promising therapeutic drug delivery system.

  12. Seasonal biodiversity of pathogenic fungi in farming air area. Case study.

    PubMed

    Plewa, Kinga; Lone, Elzbieta

    2011-01-01

    Poultry production proved to be a significant source of bioaerosols. The exposure to high concentration of microorganisms in the air can cause primarily irritations, infections, allergies, and toxic effects. The aim of the present study was to investigate the seasonal biodiversity of airborne fungi in the poultry house, in the surrounding area, as well as to estimate health risk. Seasonal investigations were conducted in the spring, summer, autumn and winter 2010 in the poultry house located near Wrocław in Lower Silesia (Poland). The air samples were collected with the use of a Merck MAS-100 onto nutrient Sabouraud agar and were incubated for 5 days at 26 degrees C. Subsequently the colony-forming units (CFU) were determined. The identification of the isolated fungi was made in accordance with the standard procedures. In the summer and autumn when the weather conditions are most friendly for the spread and the development of numerous microorganisms, fungi were more abundant in the surrounding area than in early spring and winter, when both humidity and temperature were lower. The total of 26 species were analysed (10 in the poultry house and 17 in the surrounding areas). Among 12 fungal genera: Aspergillus, Penicilium, Alternaria, Exophiala, Mycelia sterilla, Fusarium, Cladosporium, Scopulariopsis, Chaetomium, Acremonium, Candida and Rhodotorula nearly everything occurred to be the potential respiratory allergens.

  13. Graduate student voice use and vocal efficiency in an opera rehearsal week: a case study.

    PubMed

    Schloneger, Matthew J

    2011-11-01

    The purpose of this case study was to document graduate voice students' (N=2) voice use before, during, and after an intense week of opera rehearsals through (1) acquired Ambulatory Phonation Monitor (APM) data, (2) daily surveys, (3) participant activity logs, (4) three administrations of the Singing Voice Handicap Index (SVHI), and (5) pre- and post-stroboscopic laryngeal examinations. Two female graduate students, both of whom were cast in a university production of Stravinsky's The Rake's Progress (stage names Anne and Baba) and both of whom served as graduate teaching assistants in voice, wore APMs during waking hours for 9 days, including two pretest baseline days, a 5-day intensive rehearsal week just before the opera production week, and 2 baseline days after opera performances were completed. Mean phonation time dose percentages (Dt) and daily distance dose averages (Dd) were similar between the pre- and posttest periods and the intensive week. Disaggregation of acquired data by four types of activities (opera rehearsals, personal practice time, voice teaching time, and nonrehearsal or teaching time) indicated that the highest mean Dts and Dds were acquired during personal practice time and voice teaching time. Daily surveys and SVHI data as well as the pre- and post-stroboscopies indicated no notable changes occurring in vocal health. Results indicated that these singers were conscious about their voice use during periods of extensive performance demands. However, high vocal doses during voice teaching times suggest that these individuals might benefit from teacher voice care education.

  14. Multiday Transcranial Direct Current Stimulation Causes Clinically Insignificant Changes in Childhood Dystonia: A Pilot Study.

    PubMed

    Bhanpuri, Nasir H; Bertucco, Matteo; Young, Scott J; Lee, Annie A; Sanger, Terence D

    2015-10-01

    Abnormal motor cortex activity is common in dystonia. Cathodal transcranial direct current stimulation may alter cortical activity by decreasing excitability while anodal stimulation may increase motor learning. Previous results showed that a single session of cathodal transcranial direct current stimulation can improve symptoms in childhood dystonia. Here we performed a 5-day, sham-controlled, double-blind, crossover study, where we measured tracking and muscle overflow in a myocontrol-based task. We applied cathodal and anodal transcranial direct current stimulation (2 mA, 9 minutes per day). For cathodal transcranial direct current stimulation (7 participants), 3 subjects showed improvements whereas 2 showed worsening in overflow or tracking error. The effect size was small (about 1% of maximum voluntary contraction) and not clinically meaningful. For anodal transcranial direct current stimulation (6 participants), none showed improvement, whereas 5 showed worsening. Thus, multiday cathodal transcranial direct current stimulation reduced symptoms in some children but not to a clinically meaningful extent, whereas anodal transcranial direct current stimulation worsened symptoms. Our results do not support transcranial direct current stimulation as clinically viable for treating childhood dystonia.

  15. Safety of desirudin in thrombosis prevention after total knee arthroplasty: the DESIR-ABLE study.

    PubMed

    Jove, Maurice; Maslanka, Marc; Minkowitz, Harold S; Jaffer, Amir K

    2014-01-01

    Desirudin, administered 30 minutes before total hip arthroplasty is superior to enoxaparin in preventing proximal deep vein thrombosis (DVT) and pulmonary embolism (PE) with similar bleeding. The purpose of this study was to determine the safety of desirudin in patients undergoing elective total knee arthroplasty (TKA) when the first dose of desirudin was administered the evening after surgery. This is a case series of patients undergoing TKA who received desirudin 15 mg every 12 hours subcutaneously for an average of 5 days with the first dose administered postoperatively. The primary endpoint was major bleeding; secondary endpoints included wound outcomes (oozing and infection) and new symptomatic DVT or PE. Desirudin has a favorable safety profile when administered postoperatively in patients undergoing TKA with no reports of major bleeding, wound ooze, or infection. No patients experienced symptomatic DVT, but 2 patients had PE detected by computed tomography after experiencing atypical symptoms. The safety profile of desirudin is improved when administered postoperatively. Bleeding and wound outcomes seem to occur less frequently than historical desirudin and enoxaparin controls.

  16. Activity and adaptation of nitrilotriacetate (NTA)-degrading bacteria: field and laboratory studies

    NASA Technical Reports Server (NTRS)

    McFeters, G. A.; Egli, T.; Wilberg, E.; Alder, A.; Schneider, R.; Suozzi, M.; Giger, W.

    1990-01-01

    Adaptation of bacterial activity for the degradation of nitrilotriacetate (NTA) was studied using natural sediment samples and an NTA-degrading bacterium (strain ATCC 29600). Sediment samples from a river with persistent levels of NTA had much higher NTA-degradative activity than comparable samples from a less contaminated control site. When sediment from the control site was exposed to high levels of NTA a 5 day lag preceded an abrupt increase in NTA degradation while strain 29600 colonized on sand and grown in the absence of NTA became induced within eight hours. The induction of strain 29600 was compared between bacteria in suspension and cells attached to sand. The sand-associated bacteria became induced 4 to 5 h before the planktonic suspension and displayed over threefold greater specific activity. Suspensions of strain 29600 became adapted within 8 h when placed in membrane diffusion chambers that were immersed within a municipal wastewater reactor containing NTA. These findings support the concept that induction is a part of the process of bacterial adaptation to degrade NTA and sand-associated bacteria can adapt more quickly to and have a greater degradative activity for NTA than planktonic cells.

  17. In vitro studies on the development of neocortex: The influence of subcortical structures

    SciTech Connect

    Repka, A.M.

    1988-01-01

    The specific target and afferent associated survival requirements of specific populations of cortical cells growing in vitro were investigated using the technique of explant culture. Explants of rat embryonic day 14-15 posterior cortex were cultured with another cortical explant (Cx + Cx), a diencephalic explant (Cx + D) or a tectal explant (Cx + T) for 5 days in vitro (DIV). Stereological analysis of the cortical explants revealed that all cortical explants contain equal proportions of neurons, glia, neuropil, and degenerating profiles. To determine if different populations were contained in the different cocultures, HRP filling and {sup 3}H-thymidine techniques were used to characterize the cortical populations. Specific differences in the morphology of the cells and their time of origin were found in the cortical explants. To determine the underlying mechanism responsible for the differences in the cortical populations, a detailed tritiated thymidine study was undertaken. All cocultures were given a pulse of {sup 3}H-thymidine for each of the 5 DIV, and the percent of the population represented by {sup 3}H-thymidine labeled profiles and {sup 3}H-thymidine labeled degenerating profiles was determined.

  18. The treatment of Staphyloccocus aureus infected sore nipples: a randomized comparative study.

    PubMed

    Livingstone, V; Stringer, L J

    1999-09-01

    Sore, cracked nipples are commonly experienced by breastfeeding mothers. We have previously reported a strong correlation between sore, cracked nipples and S. aureus colonization. A prospective, randomized clinical trial was performed to compare four treatment regimes for S. aureus infected sore nipples. Eighty-four breastfeeding mothers were enrolled in the study. After 5 days to 7 days of treatment, only 8% of mothers showed improvement in the "optimal breastfeeding technique alone" group, 16% improved with topical mupiricin, 29% improved with topical fusidic acid, yet 79% improved with oral antibiotics (p < .0001). Optimal breastfeeding techniques and topical antibiotics ointment failed to heal most infected, sore, cracked nipples. Mastitis developed in 12% to 35% of mothers not treated with systemic antibiotics compared to 5% of mothers treated with systemic antibiotics (p < .005). In conclusion, S. aureus infected sore, cracked nipples should be diagnosed as a potentially widespread impetigo vulgaris and treated aggressively with systemic antibiotics in order to improve healing and decrease the risk of developing mastitis due to an ascending lactiferous duct bacterial infection.

  19. Sediment toxicity screening with cost-effective microbiotests and conventional assays: A comparative study

    SciTech Connect

    Vanciheluwe, M.L.; Janssen, C.R.; Persoone, G.

    1995-12-31

    A large monitoring study of freshwater sediments, using the TRIAD approach, was conducted in Flanders (Belgium). This paper reports on the results of the toxicity assessment of 80 sediment samples evaluated with a battery of microbiotests and conventional assays. Sediment pore waters, extracted by squeezing, were tested with the Microtox{reg_sign} (Vibrio fischerii) and Thamnotoxkit{trademark} F (Thamnocephalus platyurus) microbiotests and the conventional (acute) assays with algae (Selenastrum capricornutum) and daphnids (Daphnia magna). A newly developed 5 day ELS test with the catfish Clarias gariepinus was also applied to the pore waters. Solid-phase testing was performed with the Microtox Sp{reg_sign} assay and the 10 day tests with Chironomus riparius and Hyalella azteca. Uni- and multivariate statistical techniques were applied to the data matrix to select a minimal test battery from the water phase and solid phase assays and from all tests combined. The influence of sediment associated confounding factors on the validity of the test results obtained with the various assays will be discussed. Finally a comparison of the predictive power of the selected battery of signal tests and that of the complete battery will be made and the potential use of the minimal battery for the initial hazard assessment of contaminated sediments will be reviewed.

  20. Further studies on the control of ACh sensitivity by muscle activity in the rat.

    PubMed Central

    Lomo, T; Westgaard, R H

    1975-01-01

    1. Denervated rat soleus muscles were stimulated directly through chronically implanted electrodes and the influence of different amounts and patterns of stimuli on the acetylcholine (ACh) sensitivity of the muscle was studied. The number of stimuli was varied by giving similar trains of stimuli (10 Hz for 10 sec) at different intervals (0 to 12 hr). The pattern of stimulation was varied by giving different trains of stimuli (100 Hz for 1 sec, 10 Hz for 10 sec and 1 Hz continuously) as the same average frequency of stimulation (1 Hz). 2. Stimulation usually started 5 days after the denervation when ACh hypersensitivity was fully developed. Most stimulation procedures reduced extrajunctional ACh sensitivity to normal or below normal values within 5-21 days, and these levels were maintained on prolonged stimulation. 3. The rate at which ACh hypersensitivity disappeared increased with increasing amount and frequency of stimulation. However, as few as 100 stimuli given every 5-5 hr for 3 weeks caused a tenfold reduction of sensitivity. 4. The stimulation had little or no effect on the ACh sensitivity at the end plate. Along the rest of the fibre the sensitivity was reduced at approximately the same rate excep